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Chapter 11

Fetal Growth DisordersTATIANA STANISIC CHOU • JULIANNE S. TOOHEY

Intrauterine Growth RestrictionBACKGROUND • Intrauterine growth restriction (IUGR) refers to the

condition of a fetus unable to achieve its genetically determined potential size. This definition would exclude constitutionally small fetuses that would not be at risk for adverse outcome; however, often this cannot be determined absolutely until after delivery. In addition, there is a subset of fetuses that are intrinsically small and for whom intervention will not affect outcome such as in Trisomy 18. The clinical challenge is to identify a fetus that is at risk for poor outcome with the hope that modification of risk factors and appropriate interventions will improve such outcomes. We also would like to identify small but otherwise healthy fetuses in order to avoid unnecessary and inadvisable interventions.

• Incidence rate of IUGR in singleton fetuses is 3% to 7% (Romo et al, 2009) and 15% to 25% in twins (McCormick et al, 1985).

• Correct diagnosis requires accurate dating, which can be difficult and is frequently inaccurate.

• Ethnicity and racial considerations affect the expected growth rate of a fetus, which complicates population-based growth curves.

DEFINITION • Estimated fetal weight measured as less than 10th

percentile for the gestational age (small for gestational

age, or SGA) with the understanding that not all SGA infants are pathologically growth restricted and may in fact be constitutionally small. Similarly, not all fetuses that have failed to achieve their growth potential fall under the 10th percentile for the gestational age.

• Can be associated with maternal, fetal, or placental causes.

SYMMETRICAL AND ASYMMETRICAL • Symmetrical IUGR occurs during the first few months

of gestation and is caused by the failure of one or more cell cycles leaving all organ systems equally smaller in size.

• Asymmetrical IUGR occurs in the second half of the pregnancy and is associated with malnutrition and hypoxemia of the fetus.

CLASSIFICATIONS • Constitutionally small fetus measurements are

symmetrical with normal amniotic fluid. • Chromosomal and structural abnormalities, often

symmetrical measurements with aberrations of the amniotic fluid volume.

• Substrate deficiencies and placental insufficiency, usually asymmetrical growth restriction with associated oligohydramnios.

ETIOLOGIES • Fetal causes. Include genetic disorders such as

chromosomal and structural abnormalities.

1 Thrombophilias may be associated with intrauterine growth restriction (IUGR).

2 Multiple-dose steroids have been associated with growth restriction.

3 Customized growth curves should be employed when possible to allay bias in the population.

4 Doppler velocimetry has been found to be a predictor of adverse perinatal outcome.

5 In an attempt to identify a fetus in distress prior to the severe consequences of hypoxemia or acidemia, the ductus venosus has been investigated because of its rapid blood flow.

6 Several studies of long-term outcomes in IUGR infants reveal an association between lower IQ and an increase in emotional and behavioral issues. Long-term outcomes of IUGR fetuses are associated with decreased IQ as well as emotional and behavioral issues.

7 An increased incidence of the metabolic syndrome with type 2 diabetes, obesity, cardiovascular disease, and hypertension in adult life has been associated with IUGR.

K E Y U P D AT E S

98 Section 4 | The Third Trimester and Late Pregnancy Complications

• Maternal causes. Include conditions such as hypertension, renal disease, restrictive lung disease, Class F or greater diabetes, cyanotic heart disease, antiphospholipid syndrome, collagen-vascular disease, and hemoglobinopathies, which could lead to fetal hypoxemia, vasoconstriction, or decreased fetal perfusion leading to IUGR. Clinical maternal vascular disease and the presumed decrease in uteroplacental perfusion can account for 30% of growth-restricted infants.

• Other possible causes. Exposure to teratogens, malnutrition (less than 1500 kcal/day), smoking, or substance abuse (fetal alcohol syndrome strongly correlates with IUGR). Maternal cigarette smoking decreases birth weight approximately 135 to 300 gm, the fetus being symmetrically smaller. If smoking is discontinued prior to the third trimester, the deleterious effect on birth weight is reduced. Prolonged use of some medications, including steroids, Dilantin and Coumadin, has also been associated with growth restriction in the fetus. Uterine abnormalities such as fibroids or bicornuate or separated uteri are also a cause of IUGR as is prolonged exposure to high altitudes.

• Infections including viruses such as fetal rubella, Cytomegalovirus, and varicella are a cause for intrauterine growth restriction. Additionally protozoal infections such as Toxoplasma gondii and Toxoplasma cruzi as well as syphilis are other possible causes. Bacterial infections are not shown to cause IUGR.

• Multiple gestations are associated with an increased risk for intrauterine growth restriction as well as a progressive decrease in fetal and placental weight as the number of offspring increases. IUGR can be seen in both monochorionic and dichorionic twins. Twins are considered discordant when there is greater than 20% difference in growth. There is no established standard for what amount of discordance is significant.

Studies have shown that compared to symmetric twins, asymmetric discordant twins are at higher risk for adverse outcomes (Dashe et al, 2000). However, each dichorionic twin must be assessed individually, as each fetus follows its own growth velocity curve. Normal growth velocity in each twin is of greater importance than a discordant measurement between the two fetuses. Monochorionic twins must be evaluated in light of possible vascular anastomoses. Severe IUGR can be seen as part of the twin-twin transfusion syndrome. Early diagnosis is essential in order to manage complications related to this condition.

• Primary placental disease can also be related to IUGR often leading to impaired perfusion because of conditions such as placenta previa, hemangiomas, abruption, or infarcts. IUGR without other abnormalities is usually associated with a small placenta with diminished diffusing capacity. Abnormal cord insertions such as velamentous and marginal cord insertions are other causes of IUGR.

SCREENING • Lagging fundal height noted during prenatal exam is

typically the first indication but is often inaccurate and should only be used for screening.

• Essentially, all pregnant women will be screened by measuring fundal height when receiving prenatal care. which at 32 to 34 weeks’ gestational age provides 96% specificity and 70% to 85% sensitivity (Leeson et al, 1997).

• Those women with previous IUGR pregnancies should be screened by ultrasound because of their increased risk. The recurrence rate for IUGR in a previous pregnancy is nearly 20% (Berghella et al, 2007).

DIAGNOSIS • Estimated fetal weight by ultrasound • Head-to-abdomen or femur-to-abdomen ratios • Growth velocity tracked over time • Evaluation of amniotic fluid

EVALUATION • Detailed anatomic survey • Consideration for fetal karyotyping • TORCH titers if viral infection is suspected

U P D AT E # 1

Thrombophilias have shown some correlation with IUGR. Meta-analysis (Howley et al, 2005) found an association with factor V Leiden and prothrombin gene mutation; however, more recent studies show no relationship.

U P D AT E # 3

The use of population-based growth curves has been the standard. However, there is currently much discussion of customized growth curves to allay bias in the population. Some portion of the variability in fetal birth weight can be attributed to fetal and maternal factors including gender of the fetus, ethnicity, maternal body habitus, age, and education. Studies (Gardosi et al, 2009) have found that 33% of the babies identified as IUGR by the customized curve were not recognized by the population-based curve, and 26% of those were born prematurely. Additionally, 17.2% of those found to be IUGR by the population-based curve were within normal growth patterns by the customized standards and were born without any of the studied adverse outcomes. Multicenter investigations sponsored by the National Institute of Child Health and Development (NICHD) and the World Health Organization (WHO) are under way to address these issues sonographically.

U P D AT E # 2

Steroids have been used to improve fetal morbidity and mortality by advancing fetal lung maturity in preterm births. The practice of repeated dosing became commonplace in the United States despite a lack of evidence for its necessity. Studies have shown that the group receiving repeat courses of beta-methasone, specifically four or more doses, had a birth weight reduction of 95 g (Wapner et al, 2006), which was not seen in the group receiving zero to three doses. Repeated steroid dosing more commonly resulted in birth weight below the 5th and 10th percentiles for gestational age. This study also failed to show any benefit to repeated dosing compared to placebo. A single rescue course of steroids given prior to 33 weeks was shown to improve outcome without increased short-term risk (Garite et al, 2009).

99Chapter 11 | Fetal Growth Disorders

• Consider amniotic viral DNA testing • Consider a thrombophilia workup, though this is

controversial

FETAL EVALUATION • Nonstress testing (NST) • Biophysical profile (BPP) • Contraction stress test • Serial ultrasound exams for growth velocity every 2 to

4 weeks • Doppler velocimetry

• Umbilical artery. Providing an early sign of IUGR, umbilical artery Doppler indicates vascular blockage at the placenta by measuring the systolic/diastolic ratio. As more of the vasculature is affected, the end diastolic flow decreases until it is eventually absent or reversed, which is an indication of fetal vascular distress with a potentially fatal outcome (Hoffman et al, 2009).

• Middle cerebral artery. Once umbilical artery blood flow is found to be abnormal, the middle cerebral artery is examined to look for brain sparing resulting from blood shunting to the brain in the condition of hypoxemia or hypercapnia. In 2008, Mari and Hanif found that the middle cerebral artery peak systolic velocity consistently showed an increase in blood velocity and then a decrease immediately prior to fetal demise.

• Staging (Mari et al, 2008). • Stage I: Normal NST and umbilical artery Doppler

show no hypoxemia or fetal acidosis. • Stage II: Normal NST and abnormal umbilical artery

Doppler found 5% rate of hypoxia or acidosis. • Stage III: Abnormal NST and umbilical artery

Doppler found a rate of 60% hypoxia or acidosis.

TREATMENT • There has been limited success in treating fetal growth

restriction. Gulmezoglu and colleagues reported a

meta-analysis in 1997 that found three interventions improving fetal growth. These included strategies to decrease smoking, providing nutritional supplements for undernourished women, and treating malaria when this was found to be the etiology for the growth restriction.

• Pollack and colleagues reported in 1997 on in-hospital bed rest and found no improvement in fetal condition.

• The only treatment that has improved neonatal outcome is administration of steroids when premature delivery is anticipated. Bernstein reported similar benefits in the growth-restricted infant compared to its normally grown counterpart.

• Recent reports have noted that there may be a subset of particularly at-risk fetuses. In 2004, Simchen et al. noted that after administration of steroids in a group of chromosomally normal IUGR fetuses with either absent or reverse diastolic flow, 45% had a transient improvement in the Doppler waveform. This group had significantly better outcomes than the group that had no improvement.

• Despite the theoretic benefits of aspirin to treat or prevent IUGR, studies are conflicting, and as such the role of aspirin is undetermined.

MANAGEMENT • Once IUGR is diagnosed, serial exams should

be conducted including non-stress test (NST), biophysical profile (BPP), and ultrasound to follow the development of the fetus and track its condition. Steroids are given when preterm delivery is anticipated.

• Timing of delivery depends on several factors: • Abnormal fetus. Timing depends on etiology and

desire to intervene. • Placental insufficiency. Depends on growth velocity,

gestational age, fetal status, and lung maturity. • Term or near term. Deliver for preeclampsia, for no

growth over 2 to 4 weeks, for BPP of 6 or less, and for absent end or reverse diastolic blood flow.

• Remote from term. Individualization is made based on gestational age and fetal status.

• Constitutionally small fetus. If a fetus has normal growth velocity on serial ultrasounds, symmetrical measurements, no abnormalities, and normal amniotic fluid volume, expectant management can be employed.

OUTCOME • IUGR is associated with an increase in fetal

morbidity and mortality, including the need for induction, fetal compromise during labor, cesarean section, iatrogenic prematurity, and stillbirth. Gardiosi and colleagues noted in 1998 that nearly 40% of stillbirths with no abnormalities were small for gestational age.

• Morbidity for neonates with IUGR includes increased rates of thrombocytopenia, temperature instability, necrotizing enterocolitis, and renal failure.

• Considerations for long-term outcome of these infants include developmental, academic and physical growth.

U P D AT E # 4

Doppler velocimetry was found to be the best predictor of adverse perinatal outcome in IUGR (Gonzalez et al, 2007). Indi-ces used for Doppler evaluation include systolic/diastolic ratio, the resistance index (systolic velocity—diastolic velocity/systolic velocity) and the pulsatility index (systolic velocity—diastolic velocity/mean velocity) (Hoffman et al, 2009).

U P D AT E # 5

In an attempt to identify a fetus in distress prior to the severe consequences of hypoxemia or acidemia, the ductus venosus has been investigated because of its rapid blood flow. Using color and duplex Doppler to identify abnormal blood flow or reversed or absent end-diastolic flow has been suggested as an indicator for delivery; however, this remains in debate (Mari et al, 2008). Mari and Picconi have argued against using ductus venosus reverse flow (DVRF) for delivery indications prior to 32 weeks’ gestation, noting that acidemia is uncommon in DVRF fetuses and each week of gestation between 25 and 29 weeks significantly decreases mortality.

100 Section 4 | The Third Trimester and Late Pregnancy Complications

SUGGESTED READINGSIUGREtiologies

Dashe JS, McIntire DD, Santos-Ramos R, Leveno KJ: Impact of head- to-abdominal circumference asymmetry on outcomes in growth-discordant twins, Am J Obstet Gynecol 183(5):1082–1087, 2000.

Garite T: Impact of a “rescue course” of antenatal steroids: a multicenter randomized placebo-controlled trial, Am J Obstet Gynecol 200(3), 248.e1–e9, 2009.

Howley H, Walker M, Rodger M: A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction, Am J Obstet Gyn 192:694–708, 2005.

McCormick MC, Richardson DK: Access to neonatal intensive care, Future Child 5(1):162–175, 1995.

Romo A, Carceller R, Tobajas J: Intrauterine growth retardation (IUGR): epidemiology and etiology, Pediatr Endocrinol 6(Suppl 3):332–336, 2009.

Wapner R, Sorokin Y, Thom E, et al: Single versus weekly courses of antenatal corticosteriods: evaluation of safety and efficacy, Am J Obstet Gyn 195(3):633–642, 2006.

IUGRScreening

Berghella V: Prevention of recurrent fetal growth restriction, Obstet Gynecol 110(4):904–912, 2007.

Leeson S, Aziz N: Customised fetal growth assessment, Br J Obstet Gynaecol 104(6): 648–651, 1997.

IUGRFetalEvaluation

Gardosi J, Francis A: Adverse pregnancy outcome and association with small for gestational age birthweight by customized and population-based percentiles, Am J Obstet Gynecol 201(1), 2009. 28.e1–8.

Gonzalez J, Stamilio D, Ural S, et al: Relationship between abnormal fetal testing and adverse perinatal outcomes in intrauterine growth restriction, Am J Obstet Gynecol 196(5):e48–e51, 2007.

Hoffman C, Galan H: Assessing the at-risk fetus: Doppler ultrasound, Curr Opin Obstet Gynecol 21(2):161–166, 2009.

Mari G, Hanif F: Fetal Doppler: umbilical artery, middle cerebral artery, and venous system, Semin Perinatol 32(4):253–257, 2008.

Mari G, Picconi J: Doppler vascular changes in intrauterine growth restriction, Semin Perinatol 32(3):182–189, 2008.

IUGRTreatmentandManagement

Bernstein IM, Horbar JD, Badger GJ, et al: Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network, Am J Obstet Gynecol 182(1 Pt 1):198–206, 2000.

Gülmezoglu M, de Onis M, Villar J: Effectiveness of interventions to prevent or treat impaired fetal growth, Obstet Gynecol Surv 52(2):139–149, 1997.

Pollack RN, Yaffe H, Divon MY: Therapy for intrauterine growth restriction: current options and future directions, Clin Obstet Gynecol 40(4):824–842, 1997.

Simchen MJ, Alkazaleh F, Adamson SL, et al: The fetal cardiovascular response to antenatal steroids in severe early-onset intrauterine growth restriction, Am J Obstet Gynecol 190(2):296–304, 2004.

IUGROutcome

Barker D, Gluckman P, Godfrey K, et al: Fetal nutrition and cardiovascular disease in adult life, Lancet 341(8850):938–941, 1993.

Gardosi J, Mul T, Mongelli M, Fagan D: Analysis of birthweight and gestational age in antepartum stillbirths, Br J Obstet Gynaecol 105(5):524–530, 1998.

Pallotto E, Kilbride H: Perinatal outcome and later implications of intrauterine growth restriction, Clin Obstet Gynecol 49(2):257–269, 2006.

Tideman E, Marsál K, Ley D: Cognitive function in young adults following intrauterine growth restriction with abnormal fetal aortic blood flow, Ultrasound Obstet Gynecol 29(6):614–618, 2007.

U P D AT E # 6

Evaluating several published studies of long-term outcomes of IUGR infants, the Perinatal Outcome and Later Implications of Intrauterine Growth Restriction publication (Pallotto et al, 2006) noted several long-term complications for these children. Studies of the IQ of IUGR infants and their average-sized controls have generally found an association between IQ and IUGR resulting in a four- to eight-point decrease in IUGR infants. Abnormal Doppler studies in IUGR have also been associated with impaired cognitive function (Tideman et al, 2007). Additionally, greater emotional and behavioral issues have been reported in IUGR infants.

U P D AT E # 7

Several articles have reported an increased incidence of the metabolic syndrome with type 2 diabetes, obesity, cardiovascular disease, and hypertension in adult life associated with IUGR (Barker et al, 1993). The pathophysiology is not completely understood; however, it is thought that intrauterine malnutrition results in insulin resistance and a predisposition to type 2 diabetes.