Special Feature: Intrauterine Growth Restriction
Special Feature
Intrauterine Growth Restriction
By John C. Hobbins, MD, Professor of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, is Associate Editor for OB/GYN Clinical Alert.
Dr. Hobbins reports no financial relationships relevant to this field of study.
Synopsis: Intrauterine growth restriction represents immediate and long-term threats to infants with this condition. New information from Doppler studies now provides very useful information with which to optimize management of these infants and to improve outcome.
Recently, there has been an increased focus on the identification of fetal anomalies and aneuploidy through first and early second trimester maternal testing, which has improved early identification of these disorders. However, even lumped together, fetal anomalies and aneupoloidy complicate only 1-2% of all pregnancies. Intrauterine growth restriction (IUGR) is a far more common condition that complicates 5-10% of all pregnancies and accounts for 400,000 pregnancies in the United States. IUGR should garner at least as much attention as fetal anomalies and aneuploidy because diagnosis and strategic management can have a life-long impact on infants affected by this condition.
The consequences of being born small are well documented. Smaller than average babies are subject to higher rates of perinatal death, neonatal morbidity, later cognitive and developmental problems, and even higher rates of diabetes and cardiovascular disease in adult life.
Today's standard obstetrical care includes the assessment of uterine size and, generally, at least one ultrasound examination. Unfortunately, many cases of IUGR elude detection until late in pregnancy. Lindqvist et al have found that just knowing a fetus is under-grown will decrease neonatal mortality and morbidity four-fold.1
Predisposing risk factors for IUGR are:
- Fetal growth restriction in a previous pregnancy.
- History of hypertension or preeclampsia in the current or a previous pregnancy.
- A quad screen showing increased levels of AFP, hCG, or inhibin.
- Abnormal uterine artery waveforms.
- Insufficient maternal weight gain (< 10 lb).
- A fall off in fundal height growth.
Diagnosis of IUGR
For some clinicians the terms "small-for-gestational age" (SGA) and "intrauterine growth restriction" are synonymous. Many have considered SGA to be only a neonatal label. However, for others (myself included) IUGR is reserved for those fetuses who are small and deprived (as documented by abnormal Doppler studies).
The most commonly used definition of SGA is a fetus/neonate whose estimated fetal weight (EFW) is below the 10th percentile. However, another definition, favored by European clinicians, is a fetus whose abdominal circumference (AC) is below the 5th percentile. Using the AC as the defining factor makes sense, since the liver is the organ most affected by deprivation, and IUGR fetuses have minimal deposits of subcutaneous fat around their abdominal cavities (for later thermal stability).
Estimated Fetal Weight
There are more than 50 formulas in the literature for estimated fetal weight (EFW), which put into play various measurements of the fetus; now even 3-dimensional (3-D) estimates of fetal volume have been described. Despite the smorgasbord of formulas available, the one most commonly used in the United States is a formula by Hadlock2 involving the biparietal diameter, head circumference, AC, and femur length. This four-variable formula provides a reasonable estimate of fetal weight, but with fine-tuning from 3-D ultrasound, the accuracy can be further improved. For example, Lee et al found that in 66% of cases, the 3-D formula was within 5% of the fetal weight.3 Nevertheless, with 2-D, a rough rule of thumb is that in 80% of cases, the estimated weight is within 10% of the true fetal weight.4
Other Diagnostic Avenues
Oligohydramnios. Oligohydramnios frequently accompanies IUGR, but not SGA — a useful diagnostic distinction. The logical explanation for the presence of oligohydramnios is that when the fetus spares the brain, it is at the expense of flow going downward to the kidneys. However, oligohydramnios represents a diagnostic wild card because the timing of its appearance is variable and, occasionally, it is unassociated with brain sparing. However, oligohydramnios is rarely found without severe IUGR.
Some have advocated delivery if an SGA pregnancy is associated with oligohydramnios. However, oligohydramnios is a basic sign of this condition, not the cause, nor is oligohydramnios responsible for the aftermath. Since it can appear before there is Doppler evidence of compromise, many unnecessary early deliveries would occur if this were the only reason for intervention.
We have abandoned the amniotic fluid index (AFI) in favor of a maximal vertical pocket (MVP) method for diagnosing oligohydramnios. The AFI technique, compared with the MVP, over-calls true oligohydramnios and is associated with a doubling of (unnecessary) inductions and cesarean sections without improving perinatal outcome.5
Head-to-body ratio. Years ago, Stuart Campbell described two types of IUGR based on the head-to-body (H/B) ratio.6 Generally, fetuses suffering from placentally mediated IUGR are asymmetrically small since they have relatively normal size heads but small ACs (because the liver gets shortchanged). On the other hand, constitutionally small fetuses have normal H/B ratios because they are not deprived. Unfortunately, to confuse the issue, fetuses with aneuploidy and intrauterine infection-related IUGR tend to be symmetrically small. Although this concept is often forgotten because of the overlap between various types of IUGR fetuses, it still is a useful parameter to keep in mind when sorting out SGA from IUGR.
Thigh circumference. This measurement can be done with 2-D or 3-D and, although the method has not caught on, it does represent how "beefy" the fetus is. It has been used in fetal macrosomia and, as an adjunctive variable, thigh circumference has enhanced the accuracy of formulas for EFW.7
Serial biometric evaluations. With two or more appropriately spaced ultrasound exams, a growth trajectory can be plotted for individual fetuses to determine if there is plateauing of growth. Gardosi et al elegantly enchanced the concept of diagnosing IUGR by determining whether an individual fetus matches up to his/her own ideal weight expectations according to a "customized growth potential"8 — a calculation that is based on maternal height, weight, ethnicity, and parity.
Exploring Possible Causes of IUGR
Once a fetus is determined to be SGA, there are only a few diagnoses, most of which can be sorted out from the start.
Off on dates. This is one of the most common reasons for a fetus to be seemingly small, especially in patients who present for late care. Therefore, every effort should be made through menstrual history, possible dates of conception, and early ultrasound information or pregnancy test dating, to separate the "on dates" SGA fetus from the "off on dates" appropriate for gestation (AGA) fetus. We have continued to find the trans-cerebellar diameter to be extremely useful in solving this diagnostic problem because it is the last biometric measurement to be affected by fetal deprivation — except in aneuploidy or infection. In other words, it is the closest measurement to the true gestational age.
Aneuploidy. Every SGA fetus should have a detailed ultrasonic survey looking for anomalies or markers of aneploidy. With today's comprehensive ultrasonic exams, most anomalies can be excluded. Although older screening studies have shown less than stellar identification rates for anomalies,9 there is a detection difference between the low-risk population and the high-risk population.
Once structural anomalies or aneuploidy markers have been excluded in an SGA fetus, the chance of a common chromosome abnormality is, in most cases, not worth the risk of amniocentesis. New maternal DNA tests for fetal aneuploidy are essentially risk-free. However, these newer tests only include screening for trisomies 13, 18, and 21. Trisomy 18 and 13 can be excluded by ultrasound alone. Although an occasional trisomy 21 fetus slips through without ultrasound detection, the slightly short femur of a Trisomy 21 fetus is not enough to make the fetus officially SGA.
Infection. Occasionally IUGR can be caused by an infectious process, particularly cytomegalovirus (CMV), and, therefore, when it is unclear if the placenta is responsible for SGA, considering an infectious etiology is important. An infectious cause for SGA is considered when there are ultrasound clues for a central nervous system abnormality, echogenic bowel, or if the clinician simply has a hunch. Under these circumstances, today's standard workup usually involves a full "TORCH titer." However, each part of the TORCH acronym represents a diagnostic long shot, other than CMV.
Management of IUGR
Only recently has it become apparent that there are two types of IUGR. The early IUGR has long been the center of investigative scrutiny. However, now it is quite clear that late IUGR is just as worthy of attention. Each has its own pathway to trouble.
Early IUGR — The Pathogenesis
Early IUGR is largely due to placental insufficiency, and the earlier the supply/demand mismatch occurs, the earlier IUGR manifests. Usually, in this condition, the placenta has fewer terminal villi, fewer villus branches, and smaller vascular lumens than an AGA placenta. With a compromised ability to deliver oxygen and essential nutrients to the fetus by the placenta, fetal growth falls off, leading to the diagnosis of SGA by routine ultrasound examination. Doppler investigation plays a primary role in the diagnosis of IUGR, as well as in the timing of delivery. Importantly, the risks of prematurity must be weighed against the risks of hostile intrauterine environment for this at-risk fetus.
The umbilical arteries. The two umbilical arteries encounter increased resistance in early IUGR, which can be assessed by the amount of flow during diastole. Although this is quantified by the distance (or ratio) between systole and diastole, for practical purposes the obstetrician only needs to know if there is low (more favorable), absent, or reversed flow during diastole (most ominous). Most investigators only evaluate one umbilical artery, but assessing both may be valuable since a discrepancy between the two arteries may represent under-perfusion in one portion of the placenta which, in turn, could foretell IUGR.
Middle cerebral artery (MCA). As a tributary of the internal carotid artery, the MCA is responsible for sending blood to the cortex, an area in the brain that the fetal circulation attempts to protect first when in a damage-control mode. Actually, the frontal lobe gets first priority, as evidenced by waveforms from the anterior cerebral artery.10 The cortex is next in line, and, last, the cerebellum and brainstem, which are seemingly most resistant to hypoxia. The latter can be monitored by waveforms from the vertebral artery, a spoke of the subclavian artery.11
The MCA is sampled just after it leaves the circle of Willis. As opposed to the umbilical artery, normally there is low-end diastolic flow. However, when brain-sparing occurs, resistance is lowered and end diastolic flow rises. This results in a lowered systolic/diastolic (S/D) ratio, where actual threshold values depend on gestational age. When the MCA waveform begins to look like a normal umbilical artery waveform, autoregulation has occurred and the fetus has opened up his/her cerebral vascular bed.
Simplistically, it originally had been assumed that if the brain was "spared" by the fetus, the cortex would be protected, but, as noted below, the protection is imperfect. There is now evidence of an association between brain sparing and adverse neurobehavioral outcomes.
The cerebral/placental ratio (C/P ratio). When resistance in the umbilical artery rises (but not enough to exceed preset thresholds for gestational age) and the MCA resistance drops, the relationship between the two S/D ratios (or pulsatility indices) changes. Some have found the C/P ratio to be a more sensitive index of early compromise compared to either cerebral or placental flow separately.12 However, while the method may single out pregnancies in need of further surveillance, changes in the C/P ratio occur too early for this indice to have a major role in delivery decision-making.
Ductus venosus (DV). This small vessel is the main conduit for the delivery of oxygenated blood to the right heart and sends this enriched blood across the foramen ovale to the left heart, giving a more direct access to the brain via the aorta. The DV waveform indirectly reflects intra-cardiac pressures, which in advanced IUGR are elevated because of increased afterload, inadequate perfusion of the coronary arteries, and decreased ventricular compliance. The DV goes through predictable waveform changes as the fetal condition worsens — first with decreased flow during atrial contraction, then absent flow, and, finally, reversed flow (a pre-demise finding). Earlier studies in severe IUGR employing percutaneous umbilical blood testing13 have shown that abnormal DV waveforms are associated with fetal academia, which is strongly related to neurological deficit.
Summary of data shows a common sequence of events leading to perinatal death or morbidity. There have been a few studies in which severely affected early IUGR fetuses have been followed with serial Doppler evaluation.14,15,16 In these studies, the timing of delivery had been based on non-reassuring fetal heart rate patterns alone (the standard at that time), so it was possible to follow Doppler patterns as the fetal condition worsened.
Stepwise, the first Doppler parameter to become abnormal is the umbilical artery waveform. In the mid or early third trimester, a normal umbilical artery waveform is a reasonable excluder of compromise in an SGA fetus. Decreased flow in the umbilical artery will generally occur 3 weeks or more prior to changes noted in fetal heart rate pattern — the criteria that most use for an indication for delivery.15
The next waveform to become abnormal is the MCA, showing an increase in end diastolic flow. This finding is quite variable in appearance and may never happen in less severely affected IUGR fetus.
The last Doppler waveform to become abnormal is the DV — first showing decreased diastolic flow, then eventually absent or reversed flow during atrial contraction. Often, this change occurs just prior to abnormal fetal heart rate changes. Turan et al have shown that the average time from absent or reverse flow during atrial contractions in the DV is 6 days until demise and 0 days for neurological morbidity.16 Most importantly, in a study involving more than 600 IUGR pregnancies, Baschat et al showed that the best predictor of intact survival up until 29.5 weeks was gestational age, after which the DV was the best predictor.17 In other words, the survival of infants born before 29.5 weeks is more dependent on how old they are at the time of birth, rather than on Doppler findings before birth. However, after that time DV waveforms are better at predicting survival in IUGR infants born preterm. Using another variable, biophysical profile (BPP), Baschat et al also showed an impressive relationship between beat to beat variability and fetal behavior with worsening Doppler findings, suggesting that the BPP is a useful adjunctive tool in assessing IUGR.15
Summary of sequential Doppler patterns in gradually worsening early IUGR:
- Low end diastolic flow develops in the umbilical arteries.
- C/P ratio becomes abnormal.
- MCA shows increased flow during diastole.
- There is absent or reversed end diastolic flow in the umbilical arteries.
- DV shows decreased flow during atrial contraction.
- DV show absent or reversed flow during atrial contraction.
- Non-reassuring fetal heart rate pattern develops (this may happen at the same time as the last DV changes).
The most common dependent variables in the above studies were death or immediate severe neonatal morbidity. Turan et al have shown that DV was the most potent predictor of stillbirth, but with the other Doppler variables, gestational age correlated better with immediate outcome.18 Regarding immediate neonatal morbidity, the DV again was the best predictor, but to asses later neurobehavioral outcome in survivors, the MCA may provide the best clues. For example, a recent study found that abnormal MCA, irrespective of other Doppler findings, impacted negatively on neurological assessment scales in preterm IUGR vs preterm AGA neonates.19
Late IUGR
This is defined as IUGR occurring after 34 weeks' gestation and represents a new arrival to IUGR investigation and knowledge — new, because earlier investigation strongly suggested that all placentally mediated IUGR fetuses behaved in a similar way. They don't. This is a variant of IUGR, which may be even more common than early IUGR. Late IUGR occurs when the placenta initially keeps up with fetal growth requirements throughout the early and middle portions of pregnancy, but toward the end, the fetus demands more than the placenta is capable of supplying. Consequently, the EFW falls off the normal growth curve and the AC (biometric measurement) becomes the most affected. Until recently, the umbilical artery (the first Doppler waveform to change in early IUGR) provided the warning sign as to impending IUGR. However, now there is evidence that many true late IUGR fetuses have normal umbilical artery waveforms because the problem is less about placental resistance and more about unmet fetal demand. Unfortunately, at this gestational age, the brain is vulnerable to hypoxia and recent studies show that the late IUGR fetus with normal umbilical artery waveform, but an abnormal MCA waveform, has a higher rate of neurological compromise,20 later behavioral problems,21 and a higher rate of nonreassuring fetal heart rate pattern in labor, often leading to an emergency cesarean section.22 This information should get our attention — enough to obtain an MCA Doppler waveform in the SGA fetus in late pregnancy to help with the timing of delivery — irrespective of the umbilical artery findings.
The typical chain of diagnostic events occurring in late IUGR:
- MCA shows increased EDF.
- Umbilical arteries remain normal.
- DV never shows decreased flow during atrial contractions.
Based on the above studies, I think that if the fetus is SGA, is over 35 weeks, and shows increased diastolic flow in the MCA, delivery should be a consideration. Why wait for the next shoe to drop? No, there have been no RCTs demonstrating the benefit of this approach in this type of patient, but we can no longer say that the IUGR fetus is successfully and adequately protecting the brain.
References
- Lindqvist PG, Molin J. Does antenatal identification of small-for-gestational age fetuses significantly improve their outcome? Ultrasound Obstet Gynecol 2005;25:258-264.
- Hadlock FP, et al. Sonographic estimation of fetal weight. The value of the femur length in addition to head and abdominal measurements. Radiology 1984;150:535-540.
- Lee W, et al. Birth weight prediction by three-dimensional ultrasonography: Fractional limb volume. J Ultrasound Med 2001;20:1283-1292.
- Hobbins JC. Fetal Biometry. In: Obstetric Ultrasound: Artistry in Practice. Malden, MA: Blackwell Publishing; 2008.
- Magann EF, et al. Biophysical profile with amniotic fluid volume assessments. Obstet Gynecol 2004;104:5-10.
- Campbell S, Thoms A. Ultrasound measurement of the fetal head to abdominal circumference ratio in the assessment of growth retardation. Br J Obstet Gynaecol 1977;84:165-174.
- Lee W, et al. New fetal weight estimation models using fractional limb volume. Ultrasound Obstet Gynecol 2009;34:556-565.
- Gardosi J, et al. Prospective evaluation of customized fetal growth charts. Ultrasound Obstet Gynecol 1996;4(Supl 1):96.
- Boyd PA, et al. The evolution of prenatal screening and diagnosis and its impact on in unselected population over an 18-year period. BJOG 2012;119:1131-1140.
- Cruz-Martinez R, et al. Longitudinal brain perfusion changes in near-term small-for-gestational-age fetuses as measured by spectral Doppler indices of fractional moving blood volume. Am J Obstet Gynecol 2010;203:42.e1-6.
- Morales-Roselló J, Peralta-Llorens N. Doppler study of the fetal vertebral artery in small for gestational age fetuses with intrauterine growth restriction. J Ultrasound Med2012;31:1003-1010.
- Baschat AA, Gembruch U. The cerebroplacental Doppler ratio revisited. Ultrasound Obstet Gynecol 2003;21:124-127.
- Rizzo G, et al. The value of fetal arterial, cardiac, and venous flows in predicting the pH and blood gases measured in umbilical blood by cordocentesis in growth retarded fetuses. Br J Obstet Gynaecol 1995;102:963-969.
- Hecher K, et al. Monitoring of fetuses with intrauterine growth restriction: A longitudinal study. Ultrasound Obstet Gynecol 2001;18:564-570.
- Ferrazzi E, et al. Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 2002;19:140-146.
- Baschat AA, et al. Sequence of changes in Doppler and biophysical parameters as fetal growth restriction worsens. Ultrasound Obstet Gynecol 2001;18:571-577.
- Turan OM, et al. Duration of persistent abnormal ductus venosus flow and its impact on perinatal outcome in fetal growth restriction. Ultrasound Obstet Gynecol 2011;38:295-302.
- Baschat AA, et al. Predictors of neonatal outcome in early-onset placental dysfunction. Obstet Gynecol 2007;109:253-261.
- Figueras F, et al. Neurobehavioral outcomes in preterm, growth-restricted infants with and without prenatal advanced signs of brain-sparing. Ultrasound Obstet Gynecol 2011;38:288-294.
- Oros D, et al. Middle versus anterior cerebral artery Doppler for the prediction of perinatal outcome and neonatal neurobehavior in term small-for-gestational-age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2010;35:456-461.
- Eixarch E, et al. Neurodevelopmental outcome in 2-year-old infants who were small-for-gestational age term fetuses with cerebral blood flow redistribution. Ultrasound Obstet Gynecol 2008;32:894-899.
- Cruz-Martinez R, et al. Fetal brain Doppler to predict cesarean delivery for nonreassuring fetal status in term small-for-gestational-age fetuses. Obstet Gynecol 2011;117:618-626.
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