A plan for determining if intrauterine growth restriction is present, then monitoring and delivering when and how it's best for mother and infant.
By Danielle L Tate, MD, and Giancarlo Mari, MD
Dr. Tate is a Maternal-Fetal Medicine Fellow, Department of Obstetrics and Gynecology, University of Tennessee Health Sciences Center, Memphis.
Dr. Mari is Professor and Chair, Department of Obstetrics and Gynecology, University of Tennessee Health Sciences Center, Memphis.
Intrauterine growth restriction (IUGR) refers to inability of a fetus to achieve full growth potential while in utero. Although IUGR is a common complication of pregnancy, the related terminology and diagnostic criteria remain controversial. One reason is that most IUGR studies have not differentiated between constitutionally and pathologically small fetuses. In addition, studies on the pathogenesis of IUGR often assume homogeneity in the origin, hampering understanding of underlying mechanisms. The consequence is continued ambiguity about optimal management of IUGR fetuses.
Traditionally, population-based growth curves have been used to define IUGR in the United States, with a birth weight below the 10th percentile for gestational age used as a standard definition. However, adverse outcomes and mortality are increased in infants with birth weights between 10th and 15th percentile. Conversely, many neonates whose weights are below the 10th percentile are healthy.1
Several definitions of IUGR are accepted in different areas of the world. In Europe, for example, an abdominal circumference (AC) below the 10th or the 5th percentile is the preferred diagnostic criteria, as opposed to using estimated fetal weight (EFW) to define IUGR. Published definitions include: weight at birth <2500 g, EFW <10th percentile, AC <10th percentile, EFW <10th percentile with abnormal Doppler indices in the umbilical artery or middle cerebral artery, and AC <10th percentile with abnormal umbilical artery or middle cerebral artery Doppler studies. Other diagnostic criteria employ the fetus as a control for itself 2, or use customized fetal growth standards. 3
In addition, the consequences of in utero growth deficiency do not end at birth or in infancy, but rather, continue into childhood and adult life.4 Barker and others have described an association between birth weight below the 10th percentile and development later in life of hypertension, hypercholesterolemia, coronary heart disease, impaired glucose tolerance, and diabetes.4 Therefore, the growth-restricted fetus represents an enormous potential burden for both the affected individual and for society.
Ensuring fetal well-being and determining the optimal timing for delivery of an IUGR fetus is a primary goal of fetal specialists. However, the timing of delivery of these fetuses, especially at less than 32 weeks, is controversial. Furthermore, the optimal method of fetal testing is also debatable; in the United States, the most frequently used test is the biophysical profile, whereas in Europe, cardiotocography is the preferred method.5
IUGR can be caused by several different etiologies, many of which may not be determined until time of postmortem evaluation. Accurate identification of the cause is important because it may affect future pregnancies.
Approximately 40% of total birth weight is ascribable to genetic factors, whereas the other 60% is due to fetal environmental contributions.6 Although both parents’ genes affect growth, maternal genes have the primary influence on birth weight. Johnstone et al. reported that sisters of women with growth-restricted babies tend to have growth-restricted babies as well, a phenomenon not observed in their brothers.7
In addition, women who were growth restricted or SGA at birth are at increased risk of having an IUGR fetus, and specific maternal genotypic disorders can cause growth restriction, including phenylketonuria and dysmorphic syndromes such as dwarfism. Finally, many chromosomal anomalies have been associated with IUGR. Approximately 50% of fetuses with Trisomy 13 or Trisomy 18 have fetal growth restriction. In addition, confined placental mosaicism has been associated with growth restriction.8
Growth restriction is noted in many fetuses with congenital anomalies, including cardiac malformations (as many as 50% to 80% of fetuses with septal defects), anencephaly, and umbilical artery anomalies, including abnormal cord insertions. Approximately 25% of fetuses with a 2-vessel umbilical cord weigh less than 2500 g at birth.9 Gastroschisis also is often associated with growth restriction and is present in up to 25% of cases.10
Intrauterine infection underlies 5% to 10% of IUGR.8 Worldwide, malaria accounts for the majority of infection-related growth restriction. In addition, other protozoan infections including Toxoplasma gondii, Plasmodium gondii, Plasmodium sp. and Tryanosoma cruzi have been identified as potential causes of IUGR.11 Viral infectious etiologies include cytomegalovirus, rubella, toxoplasmosis, herpes zoster, human immunodeficiency virus, varicella, and syphilis. To date, there are no specific bacterial infections associated with IUGR, but chorioamnionitis is strongly associated with symmetric growth restriction between 28 and 36 weeks’ gestation, and with asymmetric growth restriction after 36 weeks’ gestation.12
Multiple gestations carry a 25% risk of IUGR in twin pregnancies and a 60% risk for higher-order gestations.13 In addition, monochorionic pregnancies are at an additional risk of discordant fetal growth restriction because of twin-twin transfusion syndrome or unequal placental blood and nutrient sharing.
Studies have shown that severely decreased maternal caloric and protein intake during pregnancy is associated with IUGR, especially when it occurs before 26 weeks’ gestation. Glucose uptake from maternal circulation is the primary source for the fetus, and the maternal-fetal glucose concentration has been shown to increase in growth restriction.14 In addition, decreases in serum concentrations of zinc and folate have been associated with growth restriction.15 The most important “nutrient” deficiency causing IUGR is oxygen. Decreased oxygen content inhibits fetal metabolism, leading to suboptimal growth.16 Many maternal conditions, including hemoglobinopathies, chronic pulmonary disease, and severe maternal kyphoscoliosis, increase risk of IUGR.
Maternal cigarette smoking, excess alcohol ingestion (ie, 2 or more drinks daily), and illicit drug use (specifically cocaine abuse) have been associated with IUGR. Cigarette smoking symmetrically decreases birth weight by 135 to 300 g, but if stopped before the third trimester, the adverse effects are reduced.17 Exposure to certain prescribed medications, such as phenytoin, warfarin, and trimethadione, has been associated with an increased IUGR risk depending on the timing, dosage, and known teratogenic effect.
Poor uteroplacental perfusion as a result of abnormal placentation is the most common placental etiology associated with IUGR, a condition defined as placental insufficiency. However, placental insufficiency may not always be “the cause” of the problem, but rather, the consequence of a poorly understood, more global, disease process.18
Unfortunately, the process that triggers the cascade of events that causes placental insufficiency is often unknown. Placental insufficiency is characterized either by a lack of trophoblast-mediated physiologic change in uterine spiral arteries or by abnormal development of the villous vascular tree.19 In either case, as fetal oxygen demand increases, oxygen delivery to the fetal circulation falls below a critical point, and the fetus compensates by redistributing its blood flow from the body to the brain, adrenal glands, and heart.20 These events can be detected by changes in blood flow Doppler velocity studies of the fetus,21, 22 manifested first as an elevated systolic/diastolic ratio, then an absence of diastolic velocity, and finally by reversed diastolic velocity in the umbilical artery.23 Fetal cardiac performance is then compromised, which can be detected by changes in the venous flow to the heart (e.g. absence or reversed diastolic flow of the ductus venosus). If all these Doppler abnormalities are present, the fetus is at an increased risk of death.5, 24-27
Placental insufficiency is the major placental abnormality seen in IUGR but there are many other placental disorders, including abruption, infarction, hemangioma, chrioangioma, and circumvallate shape, that have been implicated.
Maternal vascular disease
Maternal medical conditions associated with vascular disease have been known to result in fetal growth restriction. These disorders include diabetes, chronic hypertension, pregnancy induced hypertension, advancing age, and morbid obesity.
Diagnosis by maternal physical examination alone has proven to be inaccurate in up to 50% of cases. A single fundal height measurement at 32 to 34 weeks’ gestation has been reported to be approximately 65% to 85% sensitive and 96% specific for detecting the growth-restricted fetus.8 When IUGR is suspected by maternal fundal height, ultrasound for EFW assessment should be performed using fetal biometry. If the EFW is below the 10th percentile, further sonographic evaluation should be performed, including Doppler flow studies, amniotic fluid assessment, and evaluation for structural abnormalities.
During initial evaluation, it is important to note whether growth restriction is symmetric, asymmetric, or a mixed pattern. Intrinsic insults that occur early in pregnancy are likely to result in a symmetric growth restriction. In contrast, an extrinsic insult occurring later in pregnancy will likely result in asymmetric growth restriction. Every effort to identify an etiology should be undertaken once the diagnosis is made.
Limitations in the categorization of IUGR can be attributed to the routine practice of grouping all growth-restricted fetuses based on fetal weight. One proposed alternative grouping is as follows: 1) small for gestational age (SGA) refers to those small fetuses with no discernible pathology and with normal umbilical artery and middle cerebral artery Doppler results; 2) growth-restriction refers to small fetuses with recognizable pathology and abnormal Doppler studies; and 3) idiopathic growth restriction applies to small fetuses with no discernable pathology and abnormal Doppler studies.28
Staging of IUGR has also been proposed.29 This classification is based on fetal biometry, Doppler cardiovascular changes, amniotic fluid volume, and clinical parameters.29 In addition, the staging system is applicable to pregnancies at any gestational age. In the proposed staging system:
· Stage 0 includes fetuses with an EFW or an AC <10th percentile. Doppler of the umbilical artery and middle cerebral artery is normal.
· Stage I includes fetuses whose EFW or AC is <10th percentile plus abnormal Doppler flow of the umbilical artery or middle cerebral artery.
· Stage II includes fetuses whose EFW or AC is <10th percentile plus absent or reversed Doppler flow of the umbilical artery.
· Stage III includes fetuses whose EFW or AC is <10th percentile plus absent or reversed Doppler flow of the ductus venosus.
Based on the amniotic fluid index, each IUGR fetus will be either A (AFI <5 cm) or B (AFI ≥ 5 cm). Figures 1 to 3 show Doppler changes in IUGR fetuses.
· Stage 0 SGA fetuses have a good prognosis. They are managed as outpatient with Doppler assessment every 2 weeks. If the Doppler remains normal, delivery is recommended at term. If the Doppler becomes abnormal, these fetuses are managed as Stage I IUGR fetuses.
· Stage I IUGR fetuses are considered to have mild growth restriction, and affected mothers who are without preeclampsia are usually managed as outpatients. Antenatal corticosteroids should be given at time of diagnosis. In these fetuses, twice-weekly antenatal testing is recommended. If the non-stress testing (NST) remains reactive and the AFI remains >5.0 cm, delivery is recommended at 37 weeks’ gestation. If the umbilical artery Doppler becomes absent, these fetuses should be managed as Stage II IUGR.
· Stage II IUGR fetuses should be managed as inpatients. During hospital admission, the fetuses should undergo daily antenatal testing with twice-daily NST and daily biophysical profile (BPP). If the NST remains reassuring and the BPP score remains between 6 and 8 of 8, continuation of expectant management is recommended. In addition, antenatal corticosteroids should be given at time of diagnosis. Delivery is recommended at 34 weeks. If any of the aforementioned NSTs become non-reassuring or if the BPP score is 4 of 8 on 2 occasions at least 4 hours apart, immediate delivery is recommended. Delivery should occur via cesarean delivery because fetuses with an absent/reversed flow of the umbilical artery will not tolerate labor induction.
· Stage III IUGR fetuses are managed the same as Stage II except for delivery at 32 weeks’ gestation, regardless of gestational age at time of diagnosis. As with Stage I and II, antenatal corticosteroids should be given at time of diagnosis.
The advantage of the above scoring system is its simplicity. Only fetal biometry, sonographic interrogation of three fetal vessels, and the amniotic fluid index are needed. It also allows classification of all small fetuses. Of note is that if the umbilical artery and middle cerebral artery Doppler is normal, it is determination of flow velocity waveforms of the ductus venosus is unnecessary because it will be normal as well. The presence of IUGR in the setting of preeclampsia should not deter standard management of preeclampsia.
It is important to note the rate of mortality in the staging system.29 No deaths occurred in Stage 0 or Stage I fetuses, whereas the mortality for stage III fetuses is high (50% if there was reversal of flow in the ductus venosus; 85% mortality was observed when reversal of flow in the ductus venosus was present in combination with one of the other parameters that characterize stage III), whereas the mortality in stage II IUGR fetuses was intermediate between stages I and III (Figure 4). Also, studies have shown that fetuses can survive for days or weeks with reversal of flow in the ductus venosus.29 A recent preliminary study reported that fetuses with reversal of flow in the ductus venosus will not necessarily be acidemic at birth.30 In addition, the majority of affected pregnancies have an AFI <5 cm before fetal demise occurs (Figure 5). These data came from a study in which we were able to follow very early IUGR fetuses up to the time of demise because the patients had declined intervention.
Finally, categorizing IUGR based on gestational age at time of diagnosis is a novel concept worth mentioning. IUGR fetuses are categorized as: very early IUGR (diagnosed at ≤29 weeks), early IUGR (diagnosed between >29 and <34 weeks), and late IUGR fetuses (diagnosed following 34 weeks). The notion of grouping based on gestational age is important because morbidity and mortality differ based on gestational age, even in the absence of complications. To date, this grouping concept has not been studied. However, this introductory discussion may stimulate future studies that delve into this particular classification system.
Unfortunately, it is unclear why there are different types of IUGR but there are two hypotheses that we have postulated: a) different causes for the IUGR; and b) the same cause but with different levels of severity.
Several studies have provided recommendations as to the timing of delivery for IUGR fetuses. The loss of the “brain-sparing effect” was initially considered a parameter to guide timing of delivery.31 Other studies have reported that there is a temporal sequence of Doppler changes preceding the onset of late decelerations.32 Early Doppler changes occur in all the IUGR fetuses, whereas late Doppler changes occur in idiopathic IUGR and only in a few IUGR cases diagnosed in patients with preeclampsia(Figures 6 and 7).33 In idiopathic IUGR fetuses, the changes occur one after the other and they are predictable. In preeclamptic patients, however, the changes are unpredictable, can occur in a few hours, and in most cases, do not occur because delivery is done for maternal indication.33
Few randomized controlled trials have been performed addressing when to deliver IUGR fetuses. The Growth Restriction Intervention Trial (GRIT) compared two management strategies: immediate versus delayed delivery in high-risk pregnancies when clinical uncertainty prevailed.34 The results demonstrated that differences in perinatal morbidity and mortality, neurological outcome 2 years after birth, and long-term outcome were not statistically significant between the two groups.35 However, antenatal testing via BPP and Doppler (with the exception of the umbilical artery) were not used for fetal surveillance in all cases. In addition, the growth-restricted fetuses included in the study represented a heterogeneous population because, in this study, one-fourth of the fetuses had normal umbilical artery flow velocity waveforms, indicating they may have simply been SGA.
A second randomized trial, the Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT), was performed in the Netherlands. This study compared composite neonatal morbidity and mortality of IUGR pregnancies beyond 36 weeks who underwent immediate induction of labor versus expectant management with maternal and fetal monitoring. In addition, the study analyzed severe maternal morbidity, maternal quality of life and costs, and neurodevelopmental and neurobehavioral outcomes at 2 years postnatal. The study concluded that in women with suspected IUGR at term, there were no significant differences in adverse maternal or neonatal outcomes between induction of labor and expectant monitoring.[36-40]
A recent prospective multicenter observational trial performed in Ireland found that the abnormal umbilical artery and an estimated fetal weight < 3rd percentile were associated with adverse perinatal outcome.41
At the current time, it is not possible to identify optimal timing of delivery for very premature growth-restricted fetuses. In the United States, most physicians make the decision to deliver a growth-restricted fetus based on abnormal antenatal testing, an abnormal BPP or a Category II or III NST. In terms of survival rate, the growth-restricted fetus delivered at >25 and <30 weeks is the most problematic. In our experience, growth-restricted fetuses delivered at <25 weeks’ gestation do not survive; at the other extreme, all growth-restricted fetuses survived when delivered at >30 weeks’ gestation.42
As can be noted, there is an absence of robust data to rely on to determine the optimal timing of delivery for very premature growth-restricted fetuses. It is our institution’s practice to manage our growth-restricted fetuses based on gestational stage. We deliver the very early IUGR fetuses in the presence of either a Category III NST or an abnormal BPP (4/8 confirmed at 2 hours apart in presence of Category II NST or in the presence of a BPP of 2/8 independently by the NST).
As mentioned earlier, fetuses diagnosed with Stage I or higher IUGR involving abnormal Doppler studies should be monitored closely. Antenatal testing is recommended and frequency ranges from twice weekly to multiple times daily, depending on level of severity. Delivery solely on the basis of abnormal Doppler studies has not been proven beneficial and, in most cases, fetuses with abnormal Doppler studies do well in the setting of reassuring antenatal testing. If antenatal testing is Category III, then immediate delivery is warranted.
Data seem to support cesarean delivery for a growth-restricted fetus when there is absent or reversed flow of the umbilical artery because these fetuses rarely tolerate attempts at vaginal delivery. Care must be individualized, however, because a fetus ≥34 weeks with an abnormal umbilical artery S/D ratio but a normal BPP is not likely to tolerate labor.
IUGR secondary to placental insufficiency remains a major cause of perinatal morbidity and mortality in the United States. There is no single test that appears superior to the other available tests for determining the timing of delivery of the growth-restricted fetus. At our institution, we base the decision on the category of the NST or on the abnormal BPP. We monitor severe IUGR fetuses (reversed flow of the umbilical artery and/or reversed flow of the ductus venosus) with 3 NST/day (every 8 hours) + 1 BPP/day. In addition, administration of antenatal corticosteroids in these cases is our common practice. In some cases, the fetal heart rate is continuously monitored. We believe that by gaining a few days or at least a week between 25 and 30 weeks’ gestation, we can make a difference in the future of the IUGR fetus.33
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