Intrauterine Growth Restriction (IUGR) Case File

Intrauterine Growth Restriction (IUGR) Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 24

A 22-year-old primigravida is seen in your office at 32 weeks’ gestation for a routine prenatal visit. Her gestational age was calculated by her last normal menstrual period which agreed with an ultrasound at 8 weeks’ gestation. Her pregnancy has been uneventful to date, although she has continued to smoke 1 pack or more of cigarettes daily. She relates normal fetal movement and no uterine contractions.

Physical examination reveals her height to be 5 ft 6 in, her weight to be 118 lb (53.5 kg), and her blood pressure to be 90/60 mm Hg. She has gained 10 lb (4.5 kg) since becoming pregnant. Her fundal height is 26 cm. On ultrasound, you note an estimated fetal weight of 900 g with an elevated head circumference (HC) to abdominal circumference (AC) ratio, and an amniotic fluid index (AFI) that is at the fifth percentile.

➤ What is the most likely diagnosis?

➤ What is your next step?

➤ What are potential complications of the patient’s disorder?

ANSWERS TO CASE 24:

Intrauterine Growth Restriction (IUGR)

Summary: This is a 22-year-old woman at 32 weeks’ gestation who continues to smoke cigarettes during pregnancy with poor weight gain and a growthrestricted fetus by ultrasound.

➤ Most likely diagnosis: Intrauterine growth restriction (IUGR).

➤ Next step: Evaluate fetal well-being.

➤ Potential complications: Preterm birth; fetal stress; intrauterine demise.

ANALYSIS

Objectives

1. List risk factors for IUGR.
2. Understand signs in pregnancy that may indicate a growth-restricted fetus.
3. Be able to evaluate a patient with suspected IUGR.
4. Develop a plan of management for patient whose fetus is growth-restricted.

Considerations

This gravida has multiple risks for a fetus with IUGR: She is underweight (body-mass index [BMI] = 17.4 prior to pregnancy), has had poor pregnancy weight gain (10 lb [4.5 kg]), and is a smoker.

There are many risk factors for IUGR, which may be divided into three broad categories: maternal, uterine/placental, and fetal (see Table 24–1).

Maternal factors include hypertension (HTN), cardiac disease, respiratory diseases, renal disease, anemia, toxic habits, and malnutrition. HTN—whether antecedent to pregnancy or first appearing during pregnancy—places the fetus at risk for IUGR. Cardiac and respiratory diseases may impact oxygenation; poor maternal oxygenation is associated with IUGR. Gravidas with severe anemia are at increased risk of having a fetus with IUGR. Toxic habits, such as drug and tobacco use, are potentially the most modifiable risk factors for IUGR. Evidence suggests that advanced maternal age (AMA) is a risk for IUGR.

Uterine/placental factors include abruptio, placenta previa, and infection. Abruptio is more common in women with HTN, as well as in those who smoke. Cocaine use is a risk factor for abruption. Toxoplasmosis, herpes, and parvovirus have all been associated with IUGR. Early-onset IUGR (< 20 wk) is associated with cytomegalovirus.

Table 24–1 ETIOLOGIES OF IUGR

Maternal factors: • HTN • Renal disease • Cardiac and respiratory disease • Underweight and/or poor pregnancy weight gain • Anemia • Toxic habits: cocaine, tobacco Uterine/placental factors: • Abruptio placenta • Placenta previa • Infection Fetal factors: • Multiple gestation • Aneuploidy • Syndromes • Structural malformations • Infection

Fetal factors include multiple pregnancy, aneuploidy, structural malformations, and infection. Multiple gestations are at increased risk of IUGR. Aneuploid fetuses—trisomy 13, trisomy 18, trisomy 21—are typically smaller than their euploid siblings. Many syndromes are associated with IUGR, including Russel-Silver syndrome, Bloom syndrome, and cretinism (hypothyroidism). Fetal structural malformations, such as gastroschisis or omphalocele, place the fetus at risk for IUGR. As noted above, infection is also associated with IUGR.

APPROACH TO

IUGR

The definition of IUGR is a matter of some debate. Some authors suggest a cutoff of the third percentile (2 SD below the mean) to define IUGR. Others have proposed using the fifth percentile. The most commonly used definition is a birthweight less than the 10th percentile for gestational age (GA). 

The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin 12 (January, 2000) acknowledges “confusion in terminology,” since by definition 10% of infants in a population will have birth weight less than the 10th percentile. This bulletin notes that while defining a pathologic condition using a 10th percentile cutoff makes statistical sense, it may not be clinically relevant.

The clinical challenge of greatest relevance: distinguishing the small-buthealthy fetus from the one who is compromised. Bernstein and Gabbe elegantly define the IUGR fetus as one who suffers morbidity and/or mortality associated with the failure to reach growth potential. This is in contrast to a fetus that is constitutionally small.

Early insults to fetal growth are thought to more commonly manifest as symmetric IUGR. Symmetric IUGR may be caused by aneuploidy or early transplacental infection. On the other hand, asymmetric IUGR describes a pattern with a relatively smaller abdominal circumference in comparison to the fetal head circumference, and is thought to reflect a more recent insult to fetal growth. An example of this type of situation occurs in association with hypertension developing late in the pregnancy. The patterns may ultimately merge in the setting of long-standing complications, such as preexisting hypertension.

The excess morbidity and mortality in the setting of IUGR is significant. An early study of infants born between 38 and 42 weeks with a birthweight between 1500 and 2500 g found that perinatal morbidity and mortality were up to 30 times greater than that seen in infants born between the 10th and 90th percentile. Expert commentary on this study offered the following perspective: “An infant with a weight of 1250 g at 38 to 42 weeks’ gestation has a greater perinatal mortality risk than one born of similar weight at 32 weeks.”

Some of the neonatal morbidities associated with IUGR include increased meconium aspiration, necrotizing enterocolitis, hypoglycemia, respiratory distress, hypothermia, and thrombocytopenia.

It has been suggested that IUGR has long-term consequences, beyond those seen in the immediate postnatal period. The Barker hypothesis states that undernutrition during fetal life—a time of great developmental plasticity— increases the risk of adult-onset coronary artery disease, type II diabetes, stroke, and HTN. This increased morbidity is thought to be secondary to the allocation of energy to one trait (such as brain growth) at the expense of allocation to traits such as tissue repair processes.

Screening

In this case, the patient’s lagging fundal height prompted an ultrasound, which revealed an estimated fetal weight (EFW) of 900 g. This EFW is below the third percentile for GA. 

The diagnosis of IUGR using fundal height has several limitations. Maternal size, parity, ethnic group, and bladder volume can all impact the measurement. Fundal height performs best when done by the same examiner. The accuracy of the test is limited, with observational studies reporting IUGR detection rates ranging from 28% to 86%. Fundal height is probably a reasonable screen for low-risk pregnancies. A lagging fundal height should prompt further evaluation with ultrasound.

The major limitation to ultrasound is that the predictive value of the test depends upon the prevalence of IUGR in the population being analyzed. Estimates of fetal weight that incorporate the following seem to provide the most accurate assessment of fetal weight: AC, biparietal diameter (BPD), and femur length (FL). In diagnosing IUGR, the AC is the most sensitive of these parameters. The small abdominal circumference is secondary to depletion of abdominal adipose tissue, and decreased hepatic size due to reduced glycogen storage. Most studies report reduced AC as the most sensitive single morphometric indicator of IUGR.

A key factor in the utilization of ultrasound: the time interval between measurements. The time interval between measurements has a major impact on the false-positive rate. Overutilization of ultrasound can be hazardous, as a false-positive diagnosis may lead to iatrogenic harm, that is, un-indicated preterm delivery. Mongelli et al describe the following false-positive rates for IUGR depending upon the frequency of ultrasound evaluation:

• 1-week interval—31% false-positive diagnosis of IUGR

• 2-week interval—17% false-positive diagnosis of IUGR

• 4-week interval—3% false-positive diagnosis of IUGR

Most authors suggest waiting a minimum of 2 weeks between growth scans. 

Once a diagnosis of IUGR is suspected, the clinical challenge becomes distinguishing the small and sick (IUGR) fetus from the one who is small but healthy. Several tools help make this distinction: clinical history and risk factors, the amniotic fluid index, and Doppler studies.

A detailed history and physical should unearth any factors that would increase the risk of a pathologically small fetus (see Table 24-2). In the sample

Table 24–2 EVALUATION OF IUGR

Evaluation of IUGR: • Detailed history and physical. • Close attention to current blood pressure and blood pressure trend. • Detailed fetal anatomic survey. • Amniocentesis—the specific tests will depend upon the GA.     • Karyotype: Increased risk of aneuploidy in the setting of IUGR.     • Infectious workup: Some authors have questioned the yield of an infectious workup in the setting of IUGR,would consider most strongly if IUGR presents prior to midgestation (cytomegalovirus).     • Fetal lung maturity studies: Will depend upon the GA at presentation. • Modified or complete BPP. • Umbilical artery Doppler studies. • Antenatal corticosteroids if less than 34 weeks GA. Decision for inpatient or outpatient monitoring will depend upon the clinical circumstances.

 

patient, for example, the low BMI, poor weight gain, and smoking all point toward a pathologically—rather than constitutionally—small fetus.

Pay attention to any first or second-trimester screening results, as aneuploidy is associated with IUGR. Amniocentesis is often indicated, although this will depend on the GA at presentation. While infection is associated with IUGR, the yield of an infectious workup after midgestation is low, and some authors argue that the cost is not justified unless other signs suggest infection as the etiology for IUGR.

Decreased AFI is associated with IUGR, and may be the earliest pathologic sign detected on ultrasound. Decreased perfusion of fetal kidneys and decreased urine output explain the low AFI. In general, pregnancies with the most severe oligohydramnios have the highest perinatal mortality rate, incidence of anomalies, and incidence of IUGR. There is a positive correlation between the maximum vertical pocket (MVP) of amniotic fluid and the incidence of IUGR.

• MVP > 2 cm: 6% incidence of IUGR

• MVP between 1 and 2 cm: 20% incidence of IUGR

• MVP < 1 cm: 39% incidence of IUGR

At the other extreme, polyhydramnios and IUGR has been dubbed an “ominous combination.” This combination is associated with a high rate of structural and chromosomal anomalies.

Doppler studies have proven a powerful tool in the evaluation of a suspected IUGR fetus. Increased resistance in the placental circulation manifests as increased Doppler blood flow indices in the umbilical arteries. This finding has been demonstrated by many investigators in both animal and human models.

By signaling an underlying pathology, the utilization of umbilical artery Doppler flow measurements improves clinical outcomes. Numerous trials confirm that the use of Doppler flow measurements can significantly reduce both perinatal death and unnecessary induction of labor (iatrogenic preterm birth of the small-but-healthy fetus). Absence or reversal of end-diastolic flow (AEDF, REDF) in the umbilical artery is suggestive of poor fetal condition. Conversely, normal flow is rarely associated with significant morbidity.

In a retrospective review of greater than 500 singletons with a diagnosis of IUGR, the mean GA at delivery correlated with Doppler studies:

• Normal Doppler studies: 37 weeks at delivery

• AEDF: 31 weeks at delivery

• REDF: 29 weeks at delivery

Similarly, the perinatal mortality increases as Doppler indices worsen:

• Normal Doppler studies: 1.3% perinatal mortality rate

• AEDF: 25% perinatal mortality rate

• REDF: 54% mortality rate

Some investigators advocate the addition of venous Doppler studies in evaluating the fetus with suspected IUGR. Abnormal Dopplers in the venous circulation (ductus venosus, umbilical vein) put the IUGR fetus at even greater risk of mortality. Many clinicians consider delivery before venous abnormalities develop.

Treatment

Treatment of the fetus with suspected IUGR will depend upon the clinical circumstances, particularly the GA. A physical examination—with close attention to blood pressure—will help guide management. Fetal anatomic survey and assessment of amniotic fluid are critical. Gravidas at less than 34 weeks GA should receive a course of antenatal corticosteroids. The decision for inpatient or outpatient management is difficult to generalize. Doppler studies are very useful. Antenatal testing with BPP or modified BPP—along with a repeat growth scan in 2 to 4 weeks—is suggested.

Timing of delivery is based primarily on expert opinion, and will depend on the clinical circumstances. In general, most authorities advise delivery of the term or near-term fetus with IUGR in the following settings:

• Hypertension

• Absence of growth over a 2 to 4 week window

• Nonreassuring fetal testing

• Absent or reversal of end-diastolic flow on Doppler studies

In the gravida remote from term, normal Doppler studies are reassuring. AEDF will often trigger delivery, and REDF will almost always mandate delivery. Very close monitoring is required in those situations.

Comprehension Questions

24.1 A patient with chronic hypertension (CHTN) is being followed in the third trimester with growth scans, given the increased risk for IUGR. Which of the following intervals between ultrasound evaluations balances the sensitivity and specificity of the test?

A. Daily ultrasound for EFW

B. Weekly ultrasound for EFW

C. Ultrasound for EFW every 4 weeks

D. Ultrasound for EFW every 8 weeks

24.2 In which circumstance are umbilical artery Doppler studies not indicated, based on current evidence:

A. Further evaluation of a well-dated pregnancy (sure LMP consistent with an 8-week sonogram) noted to have symmetric IUGR.

B. Further evaluation of a gravida with late entry into prenatal care (LMP given as a 2-week range, no first or second-trimester sonographic dating), but with strong clinical suspicion for IUGR (patient has CHTN and has a history of a growth-restricted newborn).

C. Further evaluation of a healthy patient seen for lagging fundal height with an EFW at the 30th percentile for GA, normal AFI.

D. Further evaluation of a patient seen for lagging fundal height with an EFW at the 30th percentile for GA, AFI of 4 cm.

24.3 A healthy P1 at 32 weeks’ of gestation has a fundal height of 27 cm.She is 58 in tall and has a BMI of 21 kg/m2. The father of the baby is 64 in tall. The EFW of 1600 g is just below the 10th percentile for age. How would you proceed?

A. Repeat ultrasound in 3 weeks.

B. Perform umbilical artery Doppler studies.

C. Perform middle cerebral artery Doppler studies.

D. Deliver without further evaluation.

24.4 A previously healthy P1 has a lagging fundal height at 35 weeks. Ultrasound reveals an EFW of 2000 g, which is below the 10th percentile for GA. She received a course of antenatal corticosteroids at 29 weeks for threatened preterm birth. Which of the following should prompt delivery?

A. An AFI of 3 cm, no single pocket measuring greater than 2 cm

B. History of childhood asthma

C. History of preeclampsia in her first pregnancy

D. Threatened preterm birth in this pregnancy

ANSWERS

24.1 C. The accuracy of ultrasound in detecting IUGR depends upon the prevalence of IUGR in the population being evaluated. Even in gravidas with HTN—a population with increased incidence of IUGR—the sensitivity of ultrasound decreases if the test is performed too frequently. When serial ultrasounds are performed, attention should be paid to the individual fetal curve. An otherwise uncomplicated pregnancy with a fetus who is consistently growing at the 10th percentile is less worrisome than a fetus who abruptly falls from the 50th to the 10th percentile for GA.

24.2 C. Umbilical artery Doppler studies have been most extensively evaluated in the setting of IUGR. Aside from their use in the management of IUGR, Dopplers may have a role in identifying patients with idiopathic oligohydramnios who are at increased risk of adverse outcome. However, in this fetus with an appropriate EFW and normal amount of amniotic fluid, the utility of Doppler studies has not been demonstrated.

24.3 B. Given that both the parents are of small stature, this fetus is likely constitutionally—not pathologically—small. However, further reassurance is needed before simply scheduling an ultrasound in 3 weeks. Attention should be paid to the mother’s medical history and habits, as well as her blood pressure. Ask the patient about fetal movement. Assess the amount of amniotic fluid, as well as the fetal anatomy. 

Note the size of the various growth parameters. Growth restriction that spares the BPD/HC—sometimes referred to as asymmetrical IUGR—may be more worrisome than a symmetrically small fetus. 

Doppler studies of the umbilical artery are particularly useful in this setting; they suggest that the fetus is likely constitutionally small. Doppler studies of the middle cerebral artery are most commonly used in the setting of suspected fetal anemia. Delivery without further evaluation is not advised.

24.4 A. Remember that the combination of IUGR and oligohydramnios is associated with a high rate of perinatal mortality. In this near-term gravida who has received a course of corticosteroids, delivery is advised.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ Estimates of fetal weight that incorporate the AC, FL, and BPD/HC most accurately assess fetal weight (Level II-2).

➤ While ultrasound is a component in the diagnosis of IUGR, it should not be used indiscriminately. The time interval between measurements has a major impact on the false-positive rate (Level II-3).

➤ Delivery is typically indicated when IUGR is coupled with oligohydramnios (Level III).

➤ Umbilical artery Dopplers is a powerful tool in distinguishing the constitutionally small fetus from the pathologically small fetus.The use of Dopplers has been shown to significantly reduce perinatal death and unnecessary induction of labor (Level I).

➤ Timing of delivery is based primarily on expert opinion, and will depend on the clinical circumstances. Hypertension, the absence of growth over a 2 to 4 week period, and nonreassuring testing typically trigger delivery. AEDF will often trigger delivery, and REDF will almost always mandate delivery (Level III).

REFERENCES

1. Barker DJ. The developmental origins of well-being. Philos Trans R Soc Lond B Biol Sci. 2004 Sep 29;359(1449):1359-1366. 

2. Baschat AA. Arterial and venous Doppler in the diagnosis and management of early onset fetal growth restriction. Early Hum Dev. 2005 Nov;81(11):877-887. 

3. Carroll BC, Bruner JP. Umbilical artery Doppler velocimetry in pregnancies complicated by oligohydramnios. J Reprod Med. 2000 Jul;45(7):562-566. 

4. Chamberlain PF, Manning FA, Morrison I, Harman CR, Lange IR. Ultrasound evaluation of amniotic fluid volume. The relationship of marginal and decreased amniotic fluid volumes to perinatal outcome. Am J Obstet Gynecol. 1984 Oct 1; 150(3):245-249. A landmark paper that described perinatal outcome in gravidas with oligohydramnios, with and without IUGR. 

5. Miller J, Turan S, Baschat AA. Fetal growth restriction. Semin Perinatol. 2008 Aug;32(4):274-280. An excellent, recent review on IUGR. Baschat has published widely on the use of Doppler in pregnancy. 

6. Mongelli M, Elk S, Tambyrajia R. Screening for fetal growth restriction: a mathematical model of the effect of time interval and ultrasound error. Obstet Gynecol 1998;92(6):908-12. 

7. Odegård RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R. Preeclampsia and fetal growth. Obstet Gynecol. 2000 Dec;96(6):950-955. 

8. Odibo AO, Nelson D, Stamilio DM, Sehdev HM, Macones GA. Advanced maternal age is an independent risk factor for IUGR. Am J Perinatol. 2006 Jul;23(5):325-328. 

9. Ott WJ. Diagnosis of IUGR: comparison of ultrasound parameters. Am J Perinatol. 2002 Apr;19(3):133-137. 

10. Owen P, Maharaj S, Khan KS, Howie PW. Interval between fetal measurements in predicting growth restriction. Obstet Gynecol. 2001 Apr;97(4):499-504. 

11. Resnik R. IUGR. Obstet Gynecol. 2002 Mar;99(3):490-496. An excellent review article on IUGR, with practical advice on management. 

12. Soregaroli M, Bonera R, Danti L, et al. Prognostic role of umbilical artery Doppler velocimetry in growth-restricted fetuses. J Matern Fetal Neonatal Med. 2002 Mar;11(3):199-203. 

13. Williams RL, Creasy RK, Cunningham GC, Hawes WE, Norris FD, Tashiro M. Fetal growth and perinatal viability in California. Obstet Gynecol. 1982 May; 59(5):624-632. 

One of the early articles to describe the influence of IUGR on increased mortality.

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