Fetal Growth Restriction

INTRAUTERINE GROWTH RESTRICTION: DEFINITIONS

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Intrauterine growth restriction (IUGR) is a condition that changes names and definitions, but unchangingly contributes significantly to perinatal mortality and morbidity. The term "IUGR" has evolved from intrauterine growth retardation to intrauterine growth restriction. This change probably better reflects the pathophysiology of this disorder and avoids the emotionally charged and frequently misunderstood term "retardation."

Definitions are useful if they establish frameworks around which to build understanding. In this chapter, IUGR will refer to the condition in which a fetus is unable to grow to its genetically determined potential size to a degree that may affect the health of the fetus. This is a functional definition that broadens the potential scope of the discussion, but also seeks to address the population at risk for poor outcomes. Individual investigators, for purposes of study, frequently use a statistical definition (ie,

CAUSES OF IUGR

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An important distinction to make when reviewing the causes of IUGR is that these factors are not identical to the factors that cause a baby to be small for gestational age (SGA) baby. Not all fetuses who are SGA (<10th percentile) have IUGR, and not all fetuses who have IUGR are SGA. For example, if a couple has had 3 term 4-kg babies and then has a 2.7-kg term baby, that infant is not SGA, but may have IUGR.

The clinician's job is to identify the fetus whose health is endangered in utero due to a hostile intrauterine environment and to intervene appropriately in a timely fashion. This job also includes identifying the small, but well, fetus and avoiding harming that fetus or the mother.

Of all fetuses who are SGA, only about 40% are at high risk of potentially preventable perinatal death (see Picture 1). Approximately 40% of fetuses are SGA are constitutionally small babies. They are statistically small but are otherwise healthy individuals. Because this diagnosis may be made with certainty only in the neonate, a significant number of fetuses who are healthy but SGA will be subjected to high-risk protocols and potentially iatrogenic prematurity. According to Burke, no significant raise in perinatal morbidity and mortality occurs in the constitutionally small neonate.

Approximately 20% of fetuses who are SGA are abnormally and intrinsically small. Examples are fetuses with trisomy 18, cytomegalovirus infection, and fetal alcohol syndrome. Our job as clinicians is to recognize these individuals, inform the parent(s), provide anticipatory guidance, and to intervene appropriately without unnecessary maternal risk. The prognosis for this group of small fetuses is most closely related to the underlying etiology.

The remaining 40% of fetuses who are SGA (and some larger fetuses that truly are growth restricted) might benefit from timely, appropriate prenatal intervention. Table 1 is a list of potential causes of IUGR (adapted form Severi).

Table 1 - Possible causes of IUGR

The majority of these causes of IUGR prevent adequate gas exchange and nutrient delivery to the fetus to allow it to thrive in utero. This process can occur primarily because of maternal disease causing decreased oxygen-carrying capacity (eg, cyanotic heart disease, smoking, hemoglobinopathy), decreased oxygen delivery system secondary to maternal vascular disease (eg, diabetes with vascular disease, hypertension, autoimmune disease affecting the vessels leading to the placenta), or placental damage resulting from maternal disease (eg, smoking, thrombophilia, some autoimmune disease). It is not possible in as many as 40% of cases to identify the cause of IUGR.

PERINATAL IMPLICATIONS OF IUGR

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IUGR causes a spectrum of perinatal complications, including fetal deaths, prematurity, neonatal death, fetal compromise in labor, neonatal morbidity, induction of labor, and cesarean section. Gardosi et al noted that almost 40% of stillborn fetuses who were not malformed were SGA. During weeks 31-33, 63% of stillborns who were not malformed were SGA. Similarly, in a cohort study in Sweden, a 10-fold increase in late fetal deaths was found among very small fetuses.

Neonates with IUGR who survive the intrauterine experience are at increased risk for neonatal morbidity and mortality. With no nutritional reserve, the fetus redistributes blood flow to sustain function and development of vital organs. This is called the brain-sparing effect and results in increased relative blood flow to the brain, heart, adrenals, and placenta, with diminished relative flow to bone marrow, muscles, lungs, the GI tract, and the kidneys. This physiology in utero produces detectable results that aid in the diagnosis and monitoring of the fetus with IUGR (see Diagnosis and Management) but also results in some of the neonatal morbidity that neonates with IUGR face. Morbidity for neonates with IUGR includes increased rates of necrotizing enterocolitis, thrombocytopenia, temperature instability, and renal failure.

The brain-sparing effect may result in different fetal growth patterns. In 1977, Campbell and Thomas introduced the idea of symmetric versus asymmetric growth. Symmetrically small fetuses were thought to have some sort of early, global insult (eg, aneuploidy, viral infection, fetal alcohol syndrome). The asymmetrically small fetus was thought to be more likely small secondary to an imposed restriction in nutrient and gas exchange.

Investigators since then have differed on the importance of this differentiation in the diagnosis and management of pregnancies where fetal growth restriction is present. Dashe et al examined this issue among 1364 infants who were SGA (20% were asymmetrically grown) and 3873 infants who were in the 25-75th percentile (ie, appropriate for gestational age [AGA]). The symmetrically grown infants who were SGA had outcomes very similar to the infants who were AGA. Table 2 is a selected list of statistically significant perinatal outcomes and events among these groups.

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Another controversial area in the literature on IUGR is whether the stress that results in IUGR also results in advanced maturation of the fetus, resulting in decreased perinatal morbidity compared to age-matched, normally grown neonates. Bernstein et al examined this issue and whether corticosteroids might benefit the fetus with IUGR. They examined almost 20,000 neonates from 196 centers using inclusion criteria of white or African American infants born between 25-30 weeks gestation without major anomalies. They used the weight threshold of 10th percentile using race and gender-specific charts. Their results are summarized in the next table.

Table 3

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The data on the effect of steroids on these outcomes are pooled for fetuses who were AGA and SGA because the data were similar for both groups. Neonates with IUGR who received steroids had an odds ratio of 0.70 for respiratory distress syndrome (RDS), while the odds ratio for fetuses who were AGA of this same outcome was 0.50. Bernstein et al found no evidence of a protective effect of IUGR on neonatal outcome and no qualitative difference in the response to steroids amongst infants who were AGA or SGA.

Increasing data supports the idea that long-term consequences of IUGR reach well into adulthood. Hales and Barker proposed the so-called "thrifty phenotype" in 1992. This idea suggests that intrauterine malnutrition results in insulin resistance, loss of pancreatic beta cell mass, and an adult predisposition to type II diabetes. Other authors found that prepubertal individuals who had infants who were IUGR at birth show a greater insulin response than pubertal individuals who had healthy growth as infants. This suggests that the increased risk of type II diabetes in adults who had restriction as infants stems, instead, from increased peripheral insulin resistance allowing the brain-sparing physiology to occur but with permanent reduction in skeletal muscle glucose transport. This ultimately results in beta-cell burnout. Whichever pathophysiology is the cause, the risk of type II diabetes is increased in adulthood among individuals who had IUGR at birth.

In addition to clear somatic potential sequelae, mental health problems may occur as a result of IUGR. In a study performed in western Australia, Zubrick et al showed that children born below the second percentile were at significant risk for mental health morbidity (odds ratio 2.9, 95% confidence interval [CI] = 1.18- 7.12), to be academically impaired (odds ratio 6.0, 95% Cl = 2.25-16.06), and to have poorer general health (odds ratio 5.1, Cl = 1.69-15.52).

DIAGNOSIS AND MANAGEMENT

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Identifying the fetus with growth restriction is important in order to obtain an opportunity to intervene and decrease the morbidity and mortality associated with IUGR.

Women with conditions that are associated with IUGR (see Table 1) should undergo serial sonography during their pregnancies. If sonography is a limited resource, it would be reasonable to obtain a scan in the middle of the second trimester (at 18-20 wk) in order to confirm dates, evaluate for anomalies, and confirm the number of fetuses). A repeat scan scheduled at 28-32 weeks gestation based on the earlier scan would allow for detection of abnormal growth, evidence of asymmetry, and supporting evidence of the brain-sparing physiology (eg, oligohydramnios, Doppler abnormalities).

For women without the risk factors noted, screening for IUGR in the clinical setting relies on symphyses-fundal height measurements. A discrepancy of 3 or more centimeters between observed and expected measurements should prompt a growth evaluation using ultrasound.

Even so, the sensitivity of fundal height measurement is limited. In an unselected hospital population, only 26% of fetuses who had SGA were suspected SGA. One study using fundal height curves that customized for maternal weight, height, and ethnicity was able to increase the detection rate from 29.2% in the control group to 47.9% in the study population. No single biometric or Doppler measurement is completely accurate in making or excluding the diagnosis of growth restriction. The diagnosis is confirmed by neonatal assessment. The fetal diagnosis is always presumptive secondary to inherent inaccuracies in fetal assessment. As Yoshida et al pointed out, these inaccuracies include (1) accuracy of predicting birth weight by ultrasound is ?10% at best, (2) not all fetuses who are SGA are IUGR, (3) individual and unpredictable changes in growth potential occur, and (4) growth distribution is a continuum and borderline individuals exist.

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Biometry

It is important to review the dating criteria before establishing which criteria to use in order to consider a fetus SGA. If dates are uncertain or unknown, it is reasonable to obtain "2 points on the growth curve." (This is true unless strong supportive data or risk factors warrant an immediate change in management plans.) If a fetus grows parallel to a standardized growth curve (even if it is below the 10th percentile) over at least a 2-week interval and all other evaluations are reassuring, the fetus probably is constitutionally small. The clinician's index of suspicion that a fetus in such a circumstance is small due to uteroplacental insufficiency may decrease, though clinical judgment is important.

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Criteria for IUGR

Each clinician must choose specific criteria for the diagnosis of IUGR. If one uses estimated fetal weight (EFW), it is important to make sure that the referent growth chart matches the patient population studied. Consider which cut off of EFW (ie, <10th percentile,

Ultrasound

Most ultrasound machines report aggregate gestational age measurements and individual parameters. Having a habit of looking at individual values as well in order to identify the asymmetrically grown fetus is critical. Abdominal circumference (AC) measurement less than 2 standard deviation below the mean appears to be a reasonable cut off. Baschat and Weiner showed that a low AC percentile had the highest sensitivity (98.1%) for diagnosing IUGR (birth weight <10th percentile). The sensitivity of EFW (birth weight <10th percentile) is 85.7%; however, AC below the 2.5 percentile had the lowest positive predictive value (36.3%) while a low EFW had a 50% positive predictive value.

Other data to examine include amniotic fluid volume. Chauhan et al found that the frequency of IUGR was significantly higher among those pregnancies at or above 24 weeks gestations. Frequency was 19% with an amniotic fluid index (AFI) below 5 and 9% in those with an AFI above 5 (odds ratio 2.13 with 95% CI= 1.10?.16).

Banks and Miller noted a significantly increased risk of IUGR in the borderline group relative to the normal group (13% vs 3.6%; rate ratio 3.9, 95% CI 1.2-16.2) with an AFI below 10. These papers reiterate much earlier work by Chamberlain et al. Using maximum vertical pocket (MVP) measurements, these authors showed an increased rate of IUGR among fetuses with decreasing MVP. An MVP measurement of greater than 2 cm had an IUGR rate of 5%, an MVP less than 2 cm had an IUGR rate of 20%, and an MVP less than 1 cm had an IUGR rate of 39%. Chamberlain et al concluded that decreased AFI may be an early marker of declining placental function. This conclusion is valid today.

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Doppler Velocimetry

Doppler velocimetry contributes to the identification of fetuses at risk of IUGR. IUGR can result from abnormal invasion of the trophoblast and inadequate changes in intrafetal blood flow. Use of uterine artery blood flow characteristics has been most widely studied in Europe.

Albaiges et al suggest that a one-stage uterine artery screening at 23 weeks gestation would be effective in identifying pregnancies that have the most adverse perinatal outcomes prior to 34 weeks gestation related to uteroplacental insufficiency. In their study of 1751 women who were seen at 23 weeks gestation for any reason, an abnormal uterine artery study included bilateral uterine artery notches or a mean pulsatility index (PI) of greater than 1.45 for the 2 arteries. These criteria were seen in approximately 7% of the population. Within this 7% were 90% of the women who later developed preeclampsia and required delivery at before 34 weeks gestation, 70% of women with a fetus below the 10th percentile who required delivery before 34 weeks gestation, 50% of placental abruptions, and 80% of fetal deaths. Importantly, the negative predictive value for these adverse events prior to 34 weeks gestation was above 99%.

Chien and colleagues did an “overview?of published studies on the efficacy of uterine artery Doppler as a predictor of preeclampsia, IUGR, and perinatal death. In reports of studies performed on low-risk women, an abnormal uterine artery Doppler result gave a likelihood ratio (LR) of developing IUGR of 3.6 (95% CI= 3.2?), while a normal test reduced the risk to below background, with a LR of 0.8 (95% CI= 0.08 -0.09). For women who a priori were at high risk, an abnormal test gave a LR of 2.7 (95% CI= 2.1-3.4) while a normal result reduced the risks by 30% (LR of 0.7, 95% CI= 0.6-0.9).

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Umbilical Artery Doppler

Umbilical artery Doppler also plays a role in helping the clinician decide whether the small baby is in trouble. Baschat and Weiner asked if abnormal uterine artery resistance improves the diagnostic accuracy of IUGR and if it identifies the small fetus at risk of chronic hypoxemia who might benefit from close surveillance. These investigators studied 308 babies with biometry (either AC less than the 2.5 percentile or EFW less than the 10th percentile) who delivered after 23 weeks gestation. The positive predictive value for IUGR was least for AC below or at the 2.5 percentile (36.6%). For EFW below the 10th percentile, positive predictive value was 50.9%, and an elevated uterine artery systolic/diastolic (S/D) ratio gave a positive predictive value of 53.3%.

The highest sensitivity (100%) for prediction of IUGR occurred with those fetuses who had a small AC and elevated S/D ratio; this combination gave a 57% positive predictive value. The combination of EFW below the 10th percentile and an elevated S/D ratio had a sensitivity of only 86.3%, but a positive predictive value of 63%. Among all presumably small fetuses with an elevated umbilical artery S/D ratio, a 10-fold increase occurred in the rate of admissions to and longer stays in neonatal intensive care units and frequency and severity of RDS.

Baschat and others observed small fetuses (AC <5th percentile) with severely abnormal umbilical artery S/D ratio (absent or reversed end diastolic flow). Their theory was that IUGR may be related to obliteration of small muscular arteries in tertiary stem villi or developmental abnormalities in the terminal villous vascular tree. Vascular endothelial damage could result in platelet consumption with resultant thrombocytopenia. Table 4 shows their data on 115 small fetuses with umbilical artery Doppler measurements performed less than 24 hours prior to delivery.

Table 4

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This study confirms that fetuses with biometry consistent with growth restriction are a high risk group (hypoxemia, distress, birth weight <3rd percentile) but that umbilical artery Doppler velocimetry can help define a particularly high-risk group. Fong and colleagues studied 297 singleton pregnancies where fetal EFW was below the 10th percentile in fetuses that lacked major anomalies. The end points were cesarean birth for fetal distress, cord pH less than or equal to 7.1, or Apgar score less than or equal to 7 at 5 minutes. These investigators studied middle cerebral artery (MCA), renal artery, and umbilical artery Dopplers. They concluded that a normal MCA Doppler may be useful to identify small fetuses who are not likely to have a major adverse outcome. The results are noted in Table 5.

Table 5

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Hershkovitz et al looked at MCA Dopplers in small fetuses. They found that those fetuses with abnormal MCA studies experienced earlier deliveries, lower birth weights, fewer vaginal deliveries, and increased admissions to the neonatal intensive care units. Importantly, only 7/16 with Doppler evidence of brain-sparing physiology had elevated umbilical artery Dopplers. This emphasized the idea that a gradient in degree of fetal redistribution exists, and that when doing Doppler studies it may not be sufficient to evaluate only the umbilical arteries.

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Multiple Parameters

Data presented supports the concept of observing multiple parameters in order to diagnose probable IUGR. Examination of overall fetal growth, individual body measurement parameters, fluid volumes, and Doppler studies (perhaps of several vessels) should allow the clinician to identify the truly abnormally small fetus at risk of fetal death or acidemia. A systematic and multimodality approach to the fetus with IUGR or possible IUGR is important.

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Therapeutic Goals

Defining the therapeutic goals is critical in planning and implementing therapeutic strategies. As Kramer and Weiner wrote, the strategy used will depend on the underlying etiology, probability of intact neonatal survival, the estimated gestational age at diagnosis, and local expertise. The probability of intrauterine death and severity of the problem also are important. Clinicians must do their best to help the patient understand the risks of and potential benefits of any possible course of action. In certain cases, inducing delivery would merely shift fetal death to neonatal death. Helping the family understand this is critical.

Once IUGR is established, no therapy is proven to allow catch-up growth in utero. Gülmezoglu, de Onis, and Villar reported results of meta-analysis of studies, the goals of which were to treat impaired growth. In this review, only the following were shown to be helpful:

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• Behavioral strategies to quit smoking results in a lower rate of low birth weight term babies at term among mothers who smoke.

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• Balanced nutritional supplements in undernourished women, and magnesium and folate supplementation (in some studies) decreased the rate of newborns who were SGA.

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• If malaria is the etiologic agent, treatment of malaria can increase fetal growth. Pollack et al also explored this topic. They concluded that no evidence exists to support in-hospital bedrest as a way to promote fetal growth.

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• Chronic tocolytic therapy, despite theoretic decreased uterine tone and, thus, possibly improved placental perfusion, also does not improve growth rates.

If the goal is to decrease perinatal morbidity and mortality without trying to effect normal or catch-up growth, other therapeutic options have been considered. Both Nicolaides and Battaglia reported on studies of maternal hyperoxygenation to prevent perinatal mortality. Using historical controls, Nicolaides showed a decrease in mortality from 85% to 20% for individuals with IUGR who received supplemental oxygen. Battaglia randomly assigned 36 fetuses with IUGR of 26-34 weeks gestation, an AC below the fifth percentile, oligohydramnios, and abnormal Dopplers either to bedrest only or to bedrest and 55% oxygen at 8 L/min. While no change in birth weight occurred, the control group had a 68% perinatal mortality and the oxygen group experienced only a 29% mortality.

Despite these studies, hyperoxygenation is poorly studied, carries potential maternal and fetal harm, and still should be considered experimental. Additional therapies that may warrant further study are maternal hemodilution and intermittent abdominal negative pressure. These also are poorly studied, carry potential maternal and fetal harm, and should be considered experimental.

Others have looked at altering the thromboxane–prostacyclin ratios by administering aspirin +/- dipyridamole to mothers of fetuses with IUGR. These studies and those examining these agents for prevention of IUGR are difficult to compare. Different doses of aspirin, use at different times in pregnancy, and different indications for use make comparison difficult; however, the following is a summary of the comparisons:

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• Trudinger performed a double-blind randomized clinical trial (RCT) using 150 mg aspirin in pregnant women with abnormal umbilical artery Dopplers. The result was an increase in birth weight of 516 g and an increase in placental weight.

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• The CLASP trial, which looked at both prevention and treatment of IUGR, showed no change in the rate of IUGR in treated and control patients using 60 mg aspirin.

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• Newnham et al also did not show a change in outcome in women receiving 100 mg aspirin compared to the placebo after the diagnosis of IUGR with abnormal umbilical artery Dopplers had been made.

Prevention of IUGR would be ideal. Prophylactic aspirin administration to women early in pregnancy has been tried in multiple studies and appears somewhat more promising in highly selected populations. Some of these studies are summarized as follows:

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• Wallenburg studied a population of women at high risk for IUGR in a nonrandomized trial using historic controls. He noted a decline in the rate of IUGR from 61.5% in the historic controls to 13.3% in those treated with aspirin and dipyridamole.

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• Sibai studied low-risk nulliparous women in a double-blind placebo-controlled randomized trial. Patients were treated from weeks 13-26 with either placebo or 60 mg/d of aspirin. This study showed a small decrease in the rate of preeclampsia but not IUGR (4.6% vs 5.8% in control) at the risk of increased chance of abruption.

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• EPREDA trial (multicenter European randomized controlled trial in high-risk women): Groups received placebo, aspirin only, or aspirin plus dipyridamole. Nodifference in the rate of IUGR was found between those receiving aspirin alone and those receiving aspirin plus dipyridamole. The control rate of IUGR was 26%; in the two groups receiving aspirin, the rate was 13%.

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• Italian study: Women considered to be at "moderate" risk of IUGR or pregnancy-induced hypertension between 16-32 weeks gestation were randomly assigned to receive either 50 mg aspirin or no treatment. No difference in any outcome studied was found between the two groups.

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• Harrington identified patients with abnormal uterine artery Dopplers at 20 weeks gestation. Participants were started on aspirin, and therapy was discontinued at 24 weeks if repeat Dopplers normalized. No difference in the rate of fetuses who were SGA below the 10th or third percentiles was found between the treated and controls groups.

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• Leitich performed a meta-analysis of 13 trials who enrolled women for prophylactic reasons. In women treated, the odds ratio for IUGR was 0.82 (95% Cl = 0.66-1.08). Among those trials in which women were hypertensive or had other risk factors, the risk of IUGR was clearly decreased. Leitich found that beginning 100-150 mg/d of aspirin at less than 17 weeks gestation decreased IUGR by about 65% and perinatal mortality by about 60%.

Despite a theoretic benefit of aspirin in many studies, it is still unclear what role, if any, aspirin has in the prevention or treatment of IUGR. At this point, the only reasonable goals in the treatment of IUGR are to deliver the most mature fetus in the best condition possible with minimal risk to the mother. Such a goal will require the use of antenatal testing in hope of identifying the fetus with IUGR before it becomes acidotic. Developing a testing scheme, following it, and having a high index of suspicion in this population when results of testing are abnormal is important. The positive predictive value of an abnormal antenatal test in the IUGR population is relatively high because the prevalence of acidemia and chronic hypoxemia is relatively high.

The protocol for antenatal testing suggested by Kramer and Weiner is but one example. It relies heavily on the use of umbilical artery Doppler. Since severely abnormal Dopplers (absent or reversed end-diastolic flow) can precede abnormal fetal heart rate abnormality by several weeks, these authors recommend the scheme in Picture 2.

The diagnosis of severe IUGR before 32 weeks gestation carries a poor prognosis and therapy must be highly individualized.

CONCLUSION

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IUGR remains a challenging problem for both the obstetrician and pediatrician. The ability to diagnose the disorder and understand its pathophysiology still outpaces the ability to prevent its complications. Most cases of IUGR occur in pregnancies where no a priori risk factors are present; therefore, the clinician must be alert to the possibility of a growth disturbance in all pregnancies. No single measurement or assessment will secure the diagnosis; a complex strategy for diagnosis and assessment is necessary. The current therapeutic goals are to deliver the baby at the maximal gestational age possible and just before acidemia or hypoxia occurs without unnecessary risk to the mother because the appropriate interventions to prevent and treat IUGR are lacking. This is an elusive goal indeed.

PICTURES

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Caption: Picture 1. Distribution of categories of small fetuses

Picture Type: Graph

Caption: Picture 2. Sample protocol for antenatal testing for intrauterine growth restriction (IUGR) at 32 weeks' gestation or greater

Picture Type: Graph

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