Diagnosis and management of intrauterine growth restriction

Clin Perinatol 31 (2004) 743–764

Diagnosis and management of intrauterine

growth restriction

Ursula F. Harkness, MD, MPH*, Giancarlo Mari, MD

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology,

University of Cincinnati, 231 Albert Sabin Way, PO Box 670526, Cincinnati, OH 45267-0526, USA

Normal growth on a cellular level is not homogeneous but rather follows a

pattern that shifts over time from rapid cellular duplication to rapid cellular

enlargement [1]. Early growth is characterized by an increase in cell number, and

this period has proportional increases in weight, protein, and DNA (phase of

hyperplasia). This phase is followed by one in which cell division slows and

existing cells enlarge (phase of hyperplasia and hypertrophy). During this time,

the increase in DNA is slower than the increase in protein and weight. During the

final phase, cell division decreases, and all further growth is due to enlargement

of cells (phase of hypertrophy). DNA does not continue to increase, although net

protein and weight do. The effects of stimuli that restrict growth may depend in

part on when in the sequence of cellular events they occur.

Fetal growth is determined by the mother, the fetus, and the placenta. Any

factor that affects one of these three environments can result in intrauterine

growth restriction (IUGR).

Dating the pregnancy

Accurate dating is the most important step in the prenatal management of

the IUGR fetus. Using the last menstrual period (LMP) to determine gestational

0095-5108/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.clp.2004.06.006

* Corresponding author.

E-mail address: [email protected] (U.F. Harkness).

U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743–764744

age is often unreliable. In one study, menstrual history could only be obtained

from 89.8% of the women enrolled, and 44.7% of these were unreliable because

of an unsure actual date of LMP, irregular menstrual cycles, recent oral

contraceptive use, or first-trimester bleeding [2]. Ultrasound performed before

18 weeks’ gestation was as good or better for prediction of estimated date of

confinement than even an optimal menstrual history—depending on the

gestational age at which the scan was performed [2].

In the first trimester, the crown-rump length (CRL) is used to estimate

gestational age. This measurement is highly accurate [3,4]. A longitudinal view

of the fetus is found, and the calipers are placed at the outer edge of the cephalic

pole and fetal rump with care not to include the yolk sac or fetal limbs. The

pregnancy should be dated by ultrasonography if there is a greater than 7-day

discrepancy between LMP and CRL [5].

In the second trimester, fetal biometry can be used to date a pregnancy

accurately. Chervenak et al [6] studied 152 singletons conceived through in vitro

fertilization. These authors used stepwise multiple linear regression to determine

the best equation for gestational age assessment using head circumference (HC),

biparietal diameter (BPD), femur length (FL), and abdominal circumference (AC)

alone or in combination. The most accurate single parameter was HC, which gave

a random error of 3.77 days. Adding AC and FL to HC slightly improved

prediction (random error 3.35 days). Based on this study, biometry should be

used to date the pregnancy if the discrepancy between LMP and ultrasound

dating is greater than 7 days in the absence of congenital anomalies and severe

growth delay.

The accuracy of a single ultrasonographic measurement for the detection of

gestational age decreases as gestational ages increases. The normal distribution of

measurements becomes wider as gestational age increases [7]. Serial ultrasound

should be performed at 3-week intervals when dating is to be determined using

third-trimester sonography.

Although precise sonographic assessment of gestational age in the third

trimester is not feasible in all cases based on fetal biometry alone, other sono-

graphic markers are currently used to estimate the gestational age. The ossi-

fication centers of various long bones are most commonly used in practice.

These centers become increasingly echo-dense and larger with advancing

gestational age. Although their presence does not give an exact gestational

age assessment, it can reassure the clinician that the pregnancy is relatively

late into the third trimester. The distal femoral epiphysis is noted at the distal

end of the femur in the plane of measurement of this bone. The distal femoral

epiphysis is never seen before 28 weeks, and it is observed in 72% of fetuses

at 33 weeks, 94% of fetuses at 34 weeks, and 100% of fetuses at 36 weeks

[8]. The proximal tibial epiphysis is seen adjacent to the head of the tibia

at its proximal end, in the plane of measurement of this bone. The proximal

tibial epiphysis is never seen before 34 weeks, and it is found in 35% of

fetuses at 35 weeks, 79% of fetuses at 37 weeks, and 100% of fetuses at

39 weeks [8]. Finally, if the proximal humeral epiphysis is greater than or equal

U.F. Harkness, G. Mari / Clin Perinatol 31 (2004) 743–764 745

to 1 mm, there is at least a probability of 0.69 that the pregnancy is at 40 to

42 weeks [9].

Estimating fetal weight

Many different formulae have been used to calculate gestational age. Two that

are commonly used are the Shepard and Hadlock formulae. The Hadlock formula

uses head circumference, abdominal circumference, and femur length to estimate

fetal weight [10]. The estimate of random error for this method is plus or minus

15% (2 standard deviations). The Shepard formula is based on BPD and AC [11].

The fetal weight estimate, once obtained, is compared with reference ranges.

A value between the 10th and 90th percentiles is usually considered normal.

These cut-offs are used in an attempt to identify fetuses at risk. Genetic and

environmental factors may influence growth, however, and thus different popu-

lations have different growth curves.

Definitions

The terms small for gestational age (SGA) and IUGR are often used inter-

changeably, although this is misleading. The growth-restricted fetus is a fetus that

fails to reach its growth potential and is at risk for adverse perinatal morbidity and

mortality. The American College of Obstetricians and Gynecologists (ACOG)

defines an IUGR fetus as a fetus with an estimated weight below the 10th

percentile [12]. Not all fetuses measuring less than the 10th percentile are at risk

for adverse perinatal outcome; many are just constitutionally small. IUGR refers

to the fetus who is SGA and displays other signs of chronic hypoxia or

malnutrition [5]. SGA is defined here as a fetus who measures less than the 10th

percentile for gestational age, whether it be because he is growth-restricted

(IUGR) or just constitutionally small. The authors will first discuss the fetus with

an estimated weight below the 10th percentile, then suggest ways to differentiate

the small fetus from the at-risk IUGR fetus and to manage the pregnancy

complicated by IUGR.

Traditionally, symmetric IUGR has been distinguished from asymmetric

IUGR [13]. The former is described as having an early onset. The insult affects

growth of skeletal, head, and abdominal measurements, because it occurs at a

time when fetal growth is affected primarily by cell division. Asymmetric IUGR,

by contrast, has its onset later in gestation, when fetal growth occurs secondary to

increases in cell size. Skeletal and head measurements are spared, but abdominal

circumference is small because of decreased liver size and subcutaneous fat.

More recently, the need to distinguish these entities has been questioned, because

it is unclear whether they can be associated with distinct causes or neonatal

outcomes [12]. One study demonstrated, however, that although the etiologies of


symmetrically and asymmetrically small fetuses overlap, the latter are at an

increased risk for neonatal and intrapartum complications [14].

Consequences of being small for gestational age

Short term

Estimated fetal weight below the 10th percentile is a leading risk factor for

fetal death [15]. As birth weight decreases from the 10th percentile to the first

percentile, perinatal morbidity and mortality increase markedly [16]. In term

infants, the rates of low 5-minute Apgars, severe acidemia, need for intubation in

the delivery room, seizures in the first 24 hours of life, sepsis, and neonatal death

increase significantly among infants at or below the third percentile for ges-

tational age [17]. In preterm infants, by contrast, there is no specific birth-weight

threshold below which neonatal morbidity and mortality are increased; rather,

respiratory distress (RDS) and neonatal death increase along a continuum with

decreasing birth weight percentile. In a retrospective review of more than

1.4 million deliveries, the risk of RDS, intraventricular hemorrhage (IVH), and

necrotizing enterocolitis (NEC) was found to increase significantly in IUGR

fetuses as compared with normally grown fetuses beginning at 34 to 35 weeks’

gestation [18]. (Because the IUGR group was found using an International

Classification of Diseases, Ninth Revision [ICD-9] code search of a large

state database, it is difficult to assess whether only IUGR or both IUGR and

SGA babies were included.)

The findings of the aforementioned study contrast with older studies that

reported that small neonates had a decreased incidence of RDS [19,20] and IVH

[20,21] when compared with appropriate-for-gestational-age preterm neonates,

suggesting that in small fetuses there is an adaptive reaction to intrauterine stress.

Another study using the Vermont Oxford Network database described a signifi-

cant increase in neonatal death, RDS, and NEC among babies whose birth weight

was less than the 10th percentile and who weighed between 500 and 1500 g, as

compared with appropriate-for-gestational-age (AGA) babies [22]. These authors

suggest that the inconsistency between their findings and those of earlier studies

may be due to the extent to which confounding variables are addressed and taken

into account.

Long term

The problems of the small fetus do not end at birth or soon after birth but

continue well into childhood and adulthood. Studies have shown that small

children have an increased rate of impaired school performance. One study

described significantly higher numbers of children with late entry into secondary

school and failure to pass or take the baccalaureate examination in the bsmallQ


group as compared with the AGA group, after controlling for maternal age,

maternal educational level, parental socioeconomic status, family size, and gen-

der [23]. Another large follow-up study of 14,189 full-term infants from the

United Kingdom showed that at 5, 10, and 16 years of age, individuals born with

a birth weight less than the fifth percentile had small but significant deficits in

academic achievement [24]. At 26 years of age, this same cohort of once SGA

babies showed lower levels of professional achievement, despite adjustment for

potential confounders.

Other studies have described an association between fetuses with weight or

height less than the 10th percentile and the development of hypertension,

hypercholesterolemia, impaired glucose tolerance, and diabetes in later life

[25–27]. In the United Kingdom, a follow-up study on 5654 men showed that

those with the lowest weight at birth and at 1 year of age had the highest death

rate from ischemic heart disease [28]. The bfetal originsQ hypothesis asserts thatchanges in the intrauterine nutritional or endocrine environment result in per-

manent alterations in structure, physiology, and metabolism that predispose the

affected individual to develop cardiovascular, metabolic, and endocrine disease

years later [26]. An endocrine-metabolic reprogramming occurs that enables

the small fetus to adapt to its adverse intrauterine environment; after birth,

nutrient abundance may lead to a metabolic syndrome and to the development of

the above-noted cardiovascular risk factors [25]. This theory is the so-called

bBarker’s hypothesis.Q

Screening for the small fetus

Fundal height assessment

Several studies have estimated that 41% to 86% of SGA babies could be

detected with routine use of symphysis-fundal height measurements [29–32].

Some of these studies used standard value curves, with the small fundal height

defined as that below the 10th percentile of standard values for gestational age.

The most common method in practice, however, uses the concept that, between

20 and 34 weeks, the fundal height in centimeters equals the gestational age in

weeks [33]. A measurement in centimeters is taken from the upper edge of the

symphysis pubis to the top of the uterine fundus. A measurement of 3 to 4 cm

below the expected number suggests inappropriate growth.

Ultrasonographic measurements

According to one meta-analysis of ultrasonographic measurements, AC and

estimated fetal weight (EFW) were the best predictors of fetal weight below the

10th percentile [34]. In high-risk populations, the sensitivity using AC of less

than the 10th percentile was 73% to 95%, whereas using EFW the sensitivity was

43% to 89%; in low-risk populations, the corresponding sensitivities were 48% to


64% for AC and 31% to 73% for EFW. In another study, AC measurements were

shown to predict small fetuses better than BPD, HC, or a combination of

parameters [35]. The sensitivity of a single AC measurement after 25 weeks for

the detection of fetuses with birth weight below the 10th percentile was 48%. In

the same study, a normal AC was found to exclude fetal growth restriction with a

false-negative rate of about 10%. Another study showed that a single AC

measurement for the detection of babies with birth weight less than the 10th

percentile was only slightly better than serial fundal height measurements

(sensitivity 83% versus 76%); the difference was not statistically significant [36].

Thus there is no clear evidence that routine ultrasound is a better screening

method for SGA than fundal height measurement in the general population.

Diagnosis of intrauterine growth restriction

The data already reported refer to fetuses with an estimated weight below the

10th percentile. When a fetus has an estimated weight below the 10th percentile

in the absence of congenital anomalies and in the presence of a normal amount of

amniotic fluid, Doppler velocimetry gives the most important information to

differentiate the truly growth-restricted fetus (IUGR) from the fetus that is

constitutionally small but otherwise normal.

Umbilical artery

Normal pregnancy is characterized by a low-resistance feto-placental system

with continuous forward flow throughout the cardiac cycle. Although several

indices to estimate vessel resistance as evaluated by Doppler ultrasonography

have been described, the most popular and the simplest of these is the systolic/

diastolic (S/D) ratio. This index is a ratio of the maximum systolic flow velocity

divided by the minimal end-diastolic flow velocity. Normal reference ranges

throughout pregnancy are reported in Fig. 1 [37]. In pregnancies complicated

by IUGR, there is a chronological process characterized by increased umbilical

artery resistance (increased S/D ratio), absent end-diastolic flow, and finally

reverse end-diastolic flow (Fig. 2). Various hypotheses have been proposed

to explain the pathophysiology of IUGR and abnormal umbilical artery Dopp-

ler velocimetry [38]: (1) reduced placental-stem artery number, (2) primary vil-

lus maldevelopment with small, hypovascular, and fibrotic terminal villi, and

(3) placental-stem vessel vasoconstriction.

Small fetuses with abnormal umbilical artery waveforms are admitted more

frequently to the neonatal intensive care unit and stay longer compared with those

small fetuses who have normal Doppler velocimetry in the umbilical artery

[39,40]. Studies have shown that the perinatal mortality rate in pregnancies

complicated by growth restriction or hypertension is higher in fetuses with

reversed end-diastolic flow (33% to 73%) or absent end-diastolic flow (9% to

41%) in the umbilical artery [41–43]. Finally, fetuses with absent and reverse

Fig. 1. Normal values for umbilical artery S/D ratios. (From Thompson RS, Trudinger BJ, Cook CM,

Giles WB. Umbilical artery velocity waveforms: normal reference values for A/B ratio and Pourcelot

ratio. BJOG 1988;95:590; with permission.)


end-diastolic flow in the umbilical artery are at increased risk for impaired mental

development, severe motor deficits, and neurodevelopmental delay [44,45].

Eleven randomized studies involving close to 7000 women were included in a

meta-analysis that compared the use of Doppler ultrasound of the umbilical artery

to no Doppler in high-risk pregnancies, many of which were complicated by

IUGR. A trend in reduction of perinatal deaths was seen (odds ratio [OR] 0.71,

95% confidence interval [CI] 0.50 to 1.01), as well as significantly fewer in-

ductions of labor and hospital admissions without untoward effects [46]. These

data prompted ACOG to endorse the use of Doppler in high-risk pregnancies.

One area of debate and research is whether Doppler can help in timing the

delivery of an IUGR fetus. The question arises: In a fetus with an abnormal

umbilical artery waveform, is it better to deliver soon after making the diagnosis

or to prolong the pregnancy? Each of these managements carries a risk—possible

intrauterine hypoxia with continuation of the pregnancy; complications of pre-

Fig. 2. Umbilical artery waveform in a fetus with (A) normal umbilical artery flow, (B) increased

resistance with an elevated S/D ratio, (C) absent end-diastolic flow, and (D) reversed end-dia-

stolic flow.


maturity with early delivery. The Growth Restriction Intervention Trial was a

randomized trial that addressed this question in 547 pregnancies between 24 and

36 weeks with singleton or multiple gestations, in circumstances where the

provider was uncertain whether to deliver [47]. The median time to delivery was

0.9 days in the deliver-now group (within 48 hours, to allow a steroid course to be

given) and 4.9 days in the expectant-management group. Total deaths before

discharge were 29 (10%) in the deliver-now group and 27 (9%) in the expectant-

management group (OR 1.1, 95% CI 0.61 to 1.8). Based on this study, no dif-

ference exists between combined antenatal and neonatal mortality rates


associated with immediate delivery and rates associated with expectant manage-

ment until the clinician is no longer uncertain that intervention is necessary.

Information on the developmental quotient of the survivors of this study at 2 years

of age will be available in the near future.

Many authors have suggested that small fetuses with normal umbilical artery

flow represent a group not at risk for adverse perinatal outcome. Most of these

babies are constitutionally small [48–50]. Recently, Baschat and Weiner [51]

reported on 308 women with ultrasonographic EFW less than the 10th percentile

or AC less than the 2.5th percentile for gestational age. Babies with abnormal

umbilical artery Doppler had increased rates of fetal distress associated with

chronic hypoxemia, RDS, and admission to a neonatal intensive care unit. The

authors suggested that antenatal surveillance may not be necessary in SGA babies

if the umbilical artery S/D ratio and amniotic fluid are normal.

One study of 167 women with small fetuses with normal umbilical artery

Dopplers randomly allocated participants to surveillance that occurred twice

weekly or every other week [52]. Although the two groups showed no differences

in neonatal morbidity, the more frequently tested group had a higher induction

rate. Unfortunately, this study did not have the power to detect clinically impor-

tant differences in neonatal outcome. These babies could not be assumed to be

simply small and healthy, because 32% were admitted to the neonatal special care

unit (range of stay 0 to 66 days, mean 4 to 5 days), 20% had hypoglycemia, and

40% had a low ponderal index at birth, despite the fact that the mean gestational

age at delivery was 38 weeks. However, 10% of the babies in this study had an

abnormal cerebral artery/umbilical artery resistance ratio, a finding that suggests

that some of them were growth-restricted babies with blood flow redistribution.

Evidence shows that umbilical artery Doppler can be used to distinguish

between the high-risk small fetus that is truly growth-restricted and the lower-risk

small fetus. A prospective randomized trial is needed to examine the question of

whether antenatal surveillance is necessary when fetal growth is less than the

10th percentile, but the umbilical artery S/D and AFI are normal.

Middle cerebral artery

The fetal response to chronic hypoxia is redistribution of blood flow to the

tissues that are most needed, such as the brain, myocardium, and adrenal glands.

This phenomenon has been called the bbrain-sparing effect.Q In this scenario,

oligohydramnios is thought to occur because of decreased renal perfusion.

Mari and Deter [53] described a parabolic pattern of middle cerebral artery

(MCA) pulsatility index ([peak systolic velocity � lowest diastolic velocity]/

mean velocity) in normal singletons across gestational age, with higher values

from 25 to 30 weeks (Table 1). These authors showed that SGA babies with

abnormal pulsatility indices were at a higher risk for perinatal death and neonatal

ICU stay of greater than 12 hours [53]. Fig. 3 demonstrates a normal MCA

waveform and one that suggests bbrain sparing.Q

Table 1

Middle cerebral artery pulsatility index

Gestational age (wk)

Normal values

Lower limita Predicted value Upper limitb

15 0.99 1.57 2.14

16 1.08 1.71 2.33

17 1.16 1.83 2.51

18 1.23 1.95 2.67

19 1.30 2.05 2.81

20 1.35 2.14 2.93

21 1.40 2.22 3.04

22 1.44 2.29 3.13

23 1.48 2.34 3.20

24 1.51 2.38 3.26

25 1.52 2.41 3.30

26 1.54 2.43 3.32

27 1.54 2.44 3.33

28 1.54 2.43 3.32

29 1.52 2.41 3.30

30 1.50 2.38 3.26

31 1.48 2.34 3.20

32 1.44 2.28 3.12

33 1.40 2.21 3.03

34 1.35 2.13 2.92

35 1.29 2.04 2.79

36 1.22 1.94 2.65

37 1.15 1.82 2.49

38 1.07 1.69 2.32

39 0.98 1.56 2.13

40 0.89 1.40 1.92

41 0.78 1.24 1.70

42 0.67 1.06 1.45

Abbreviations:GA, gestational age; PI, Pulsatility index; PI = �1.9763 +(0.32737 GA) +

(�0.00611 GA2).a Predicted value � (2 � 0.184 � predicted value).b Predicted value + (2 � 0.184 � predicted value).

From Mari G, Deter RL. Middle cerebral artery flow velocity waveforms in normal and small-

for-gestational-age fetuses. Am J Obstet Gynecol 1992;166:1268; with permission.


The IUGR fetus displays an increased placental resistance, evidenced by an

increased S/D ratio of the umbilical artery that is associated with a decreased

cerebral vascular resistance quantified by a decreased pulsatility index (PI) of the

MCA. Therefore, the cerebral-placental ratio may be a better index to assess the

small fetus than the umbilical artery or cerebral vessels [54,55]. The cerebral-

placental ratio generally refers to the ratio between the MCA PI and the umbilical

artery PI. This index, however, has alternatively been defined as the ratio of S/D

or resistance index in the MCA and umbilical artery. In small fetuses, cerebral-

placental ratio is a good predictor for longer neonatal ICU stays, low Apgar

scores, cord gas pH, cesarean for fetal distress, and other perinatal complications

[56–59]. The cerebral-placental ratio is a more sensitive predictor than either

Fig. 3. Middle cerebral artery waveform in (A) a fetus at 31 weeks with normal flow and (B) a fetus

at 32 weeks with brain sparing, as evidenced by an increased MCA diastolic flow velocity waveform

that corresponds to a decreased pulsatility index. The pulsatility index for fetus (A) is 2.02 and for

fetus (B) 0.90.


MCA or umbilical artery velocimetry alone [56–59]. Usually the cut-off cerebral-

placental ratio below which the fetus is considered to have brain sparing is 1.0 to

1.1 [56,58]. The cerebral-placental ratio does not correlate significantly with

perinatal morbidity after 34 weeks [59].

Although an abnormal cerebral Doppler is frequently seen in fetuses with

abnormal umbilical artery velocimetry, MCA redistribution may be seen in

fetuses with normal umbilical artery waveforms. One study reported an increased

rate of emergency cesarean section in small babies with normal umbilical artery

velocimetry when the MCA waveform was abnormal [60]. When the uterine

artery waveform was also abnormal, the rate of emergency cesarean was reported

to be as high as 86%, versus 4% when MCA and uterine artery velocimetry were

both normal. The rate of severe morbidity (grades II to IV intraventricular

hemorrhage) was significantly increased in the pregnancies delivered by emer-

gency cesarean section. Although abnormal umbilical artery velocimetry is a

better predictor of adverse perinatal outcome in the small fetus, MCA PI has a

better sensitivity (91.7%) and negative predictive value (98.6%) for major

adverse outcome, especially before 32 weeks (when the sensitivity is 95.5% and

the negative predictive value is 97.7%) [61].

The cerebral-placental ratio should be used in small fetuses with normal

umbilical artery waveforms. When there is absent or reversed flow of the

umbilical artery, this index is not needed.


Issues in management of intrauterine growth restriction

Ductus venosus

The ductus venosus (DV) originates from the umbilical vein before it turns

to the right to join the portal vein [62,63]. Blood from the DV then enters

the inferior vena cava. The DV waveform includes two peaks. The first peak

(S wave) reflects filling of the right atrium during ventricular systole. The second

peak (D wave) reflects the passive filling of the ventricles during early diastole.

The lowest point of the waveform (A wave) corresponds to atrial contraction

(atrial kick) in late diastole [5,62]. In the normal fetus, flow in the DV is forward-

moving toward the heart during the entire cardiac cycle. When circulatory

compensation of the fetus fails, the DV waveform may become abnormal,

showing absent or reversed blood flow (Fig. 4) during atrial contraction. In these

cases, pulsations in the umbilical vein may be seen. These changes may be due to

increasing right ventricular afterload and right-sided heart failure due to

myocardial hypoxia [62].

The perinatal mortality in the presence of absent or reversed flow of the DV

ranges from 63% to 100% [64–66]. It appears that the fetus should be delivered

before the development of absent or reversed flow of the DV. Therefore, the

inclusion of venous Doppler in antepartum surveillance for IUGR fetuses may be

beneficial, although a prospective randomized trial has not yet been done to

confirm this hypothesis [67]. In one study including 224 fetuses with IUGR who

underwent umbilical artery (UA), DV, and umbilical vein assessment, absent or

reversed UA waveform was shown to have the highest sensitivity and negative

Fig. 4. Ductus venosus velocimetry in a fetus with (A) a normal waveform and (B) reversed blood

flow during atrial contraction (arrow).


predictive value for acidemia, asphyxia, stillbirth, and neonatal and perinatal

death [67]. Absent or reversed atrial systolic blood-flow velocity in the DV and

pulsatile flow in the umbilical vein, however, had the best specificity and positive

predictive values for prediction of the above outcomes. The authors suggested

that important intrauterine time can be gained for preterm fetuses who have

absent or reversed UA end-diastolic velocities but normal venous flows.

Results of a prospective multicenter longitudinal observational study also

suggested that Doppler velocimetry of the DV may be useful in timing the

delivery of the IUGR fetus [68]. Of 70 singleton IUGR fetuses delivered between

26 and 33 weeks’ gestation, DV PI was significantly higher, UA PI was sig-

nificantly higher, and short-term heart-rate variation (STV) was significantly

lower in the last 24 hours before delivery in babies with adverse outcomes. Poor

outcomes included perinatal death, cerebral hemorrhage of grade II or greater,

and bronchopulmonary dysplasia. Two to 7 days before delivery, only DV PI was

significantly higher. With logistic regression analysis, only DV waveform and

gestational age—not UA PI or STV—were predictive of adverse outcomes. Only

32% (6/19) of the infants with DV PI of 3 standard deviations or greater and 18%

(2/11) of the infants with absent or reversed DV A-wave flow in the 24 hours

before delivery had normal outcomes.

Although the results of these studies are promising for timing the delivery of

the IUGR fetus based on DV, data from randomized trials are not yet available to

support or refute its use. Currently, a multicenter prospective randomized trial is

being planned in Europe.

Other vessels

Many other vessels have been assessed by Doppler ultrasound in the AGA and

IUGR fetus [69–77]. Those studies have improved our understanding of fetal

physiology and the pathophysiology of the IUGR fetus. However, they do not

add much beyond the information given from assessment of the UA, MCA,

and DV.

Temporal sequence of Doppler changes

Recent longitudinal studies have described a Doppler temporal sequence in

the IUGR fetus before fetal distress. Hecher et al [78] reported findings from a

prospective observational multicenter study on 93 singleton pregnancies after

24 weeks complicated by IUGR. Amniotic fluid index and UA PI were the first

to become abnormal. These were followed by abnormalities of MCAvelocimetry,

aorta Doppler studies, STV of the fetal heart rate, DV waveforms, and inferior

vena cava Doppler studies. This trend appeared both before and after 32 weeks.

In the group delivered after 32 weeks, however, the probability of having any

given abnormality in Doppler velocimetry was lower, and the changes in actual

Doppler values and STV were less pronounced.


Baschat et al [79] longitudinally studied 44 IUGR fetuses with elevated

umbilical artery PI who had a final biophysical profile of less than 6/10 before

delivery. In 42 fetuses (95.5%), one or more vascular parameters changed. UA

and DV indices markedly increased at a median of 4 days before the biophysical

score deteriorated. Fetal breathing movements declined beginning 2 to 3 days

before delivery; the following day, amniotic fluid volume dropped. Loss of fetal

movement and tone occurred on the day of delivery. In 70.5% of these fetuses,

Doppler deterioration was complete 24 hours before the biophysical profile

changed. Three patterns of Doppler deterioration were described in this study.

The majority of fetuses (72.7%) displayed a sequence of worsening of the UA

PI, development of brain sparing, then venous changes. Another group of fetuses

showed venous changes before brain sparing. Finally, some fetuses demonstrated

changes in the DV without ever showing Doppler changes consistent with

brain sparing.

Ferrazzi et al [80] evaluated 26 IUGR fetuses with abnormal uterine and UA

Doppler velocimetry. A temporal sequence of abnormal Doppler changes was

described. Early changes, assumed to reflect increased placental vascular resist-

ance and hypoxia, included absent end-diastolic flow in the UA and an abnormal

MCA PI. Half the fetuses showed these changes 15 to 16 days before delivery.

Late changes, thought to indicate circulatory collapse, were reverse flow in the

UA and abnormal DV, aortic, and pulmonary outflow tract velocimetry. Half the

fetuses were affected by these late changes 4 to 5 days before delivery. These late

Doppler changes correlated significantly with perinatal death.

Significantly, not all fetuses appear to follow the same pattern of circulatory

deterioration [79]. In addition, near-term fetuses may not show the same

progression of circulatory changes [79]. These differences need to be considered

when using Doppler velocimetry in the antenatal surveillance of the IUGR fetus.

Nonstress test

The heart rate of the fetus that is not affected by acidosis or neurologic de-

pression will accelerate in response to fetal movement. This reaction is the basis

of the nonstress test (NST). Although abnormal fetal heart-rate patterns are

related to impaired fetal oxygenation and subsequent neurologic outcome, these

are late changes. Ideally, the fetus should be delivered before evidence of

hypoxemia is noted on fetal heart-rate monitoring to avoid subsequent handicap

[81]. However, the NST remains the most common test used in evaluation of

pregnancies complicated by an IUGR fetus.

Biophysical profile

The biophysical profile (BPP) is based on the fact that the fetal central nervous

system initiates and regulates biophysical activity. Neuronal centers deprived of

oxygen have decreased or absent output, which results in alterations in fetal

movement, tone, and breathing. Systemic hypoxia is assumed to be absent as


long as brain activity is normal, because the brain is one of the most oxygen-

dependent tissues [82].

The BPP is a widely used antepartum testing modality. A significant decrease

in perinatal mortality is seen in high-risk pregnancies managed with BPP as

opposed to those managed with untested historical controls. The perinatal mor-

tality in one study was 1.86 per 1000 in those tested, compared with 7.69 per

1000 in those not tested, for a decrease of 76% [83]. In a large retrospective study

of 26,290 high-risk fetuses who received BPP testing and 58,659 fetuses who

did not receive BPP testing, there was a very significant inverse exponential

relationship between BPP before delivery and incidence of cerebral palsy [84].

The incidence of cerebral palsy when the last BPP score before delivery was

normal (10/10, 8/10, or 8/8) was 0.7 per 1000, whereas with a score of 0/10 the

incidence of cerebral palsy was 333 per 1000. In the same study, these same

high-risk fetuses were compared with mixed low-risk and high-risk patients not

followed by BPP; the rate of cerebral palsy was 4.74 per 1000 in the untested

population and 1.33 per 1000 in the tested group, a significant difference.

Although the mean birth weight is noted to be smaller in the tested population,

the actual number of SGA or IUGR fetuses in this study is unknown.

The authors of a review assessing the effects of BPP on perinatal outcome

conclude that there is currently inconclusive evidence from randomized

controlled trials to support or argue against the use of BPP as a test of fetal

well-being in high-risk pregnancies, including those with IUGR [85]. Surpris-

ingly, however, the number of patients enrolled in randomized trials using this

method of antepartum testing is small (2839).

Corticosteroids

One important consideration regarding the use of the BPP in the management

of high-risk pregnancies is the effect of corticosteroids on fetal behavior and thus

on the score itself. In a study of 35 women at risk for preterm delivery without

IUGR and between 28 and 34 weeks, BPPs and Doppler velocimetry of the UA

and MCA were performed daily before a first dose of betamethasone and for

120 hours afterward [86]. Though none of the BPPs were less than or equal to 6 at

baseline, at 24, 48, and 72 hours poststeroids, 13.3%, 76.7%, and 16.7% were

less than or equal to 6, respectively (P b 0.05). The change in BPP was due to

decreased fetal movement, decreased fetal breathing, and more frequent

nonreassuring heart-rate tracing. The alteration in BPP in these healthy fetuses

was transient. Doppler indices were not affected by corticosteroid administration.

Another prospective study showed findings of decreased fetal breathing and

decreased fetal limb and trunk movements 48 hours from a first dose of beta-

methasone, with return to baseline at 96 hours; again, Doppler velocimetry of

the MCA and UA remained unchanged [87]. These effects should be considered

in managing women with IUGR after steroids have been administered.

The efficacy of antenatal corticosteroids for the preterm fetus with IUGR has

not been well studied. One study showed no significant difference in short-term


morbidity between infants with growth restriction delivered between 26 and

31 weeks who received corticosteroids and those who did not, but it did demon-

strate a significantly higher survival without disability or handicap in the steroid

group [88]. Another study reported no difference between growth-restricted

fetuses of less than 1750 g given steroids and AGA infants for several neonatal

outcomes, including RDS and intraventricular hemorrhage/periventricular leu-

komalacia [89].

However, a very recent study demonstrated that of 19 fetuses with absent or

reversed end-diastolic flow (ARED) in the UA, 10 developed transient forward

end-diastolic flow after betamethasone injection, whereas nine fetuses showed

persistent ARED [90]. Although some babies respond to steroids with vaso-

dilation of the fetoplacental circulation and decreased vascular resistance, other

babies respond with an increase in vascular resistance that may lead to fetal

deterioration. The persistent ARED group had more frequent acute fetal deterio-

ration. The two patients with a fetal demise and the two patients with severe

acidosis were in the persistent ARED group. The authors suggest performing

Doppler studies the day after steroid administration in IUGR fetuses with ARED.

If no forward end-diastolic flow is seen, the fetal venous circulation should be

examined, and delivery should be considered if abnormalities exist. The response

of IUGR fetuses to corticosteroid administration should be studied further.

Prediction of intrauterine growth restriction

Uterine artery

IUGR and pre-eclampsia have been associated with abnormal velocimetry of

the uterine arteries. The uterine artery is typically measured using color Doppler

where it crosses over the external iliac artery. In the normal pregnancy, the normal

waveform shows high flow throughout diastole. An abnormal waveform is

characterized by high resistance and an early diastolic notch (Fig. 5). This finding

is thought to be related to a failure of trophoblastic invasion of spiral arteries and

the resultant low-resistance circulation.

One large study in 5121 unscreened women found that, at the 95th percentile

for mean PI at 23 weeks in the studied population (1.45), the likelihood ratio for

severe adverse outcomes was 5 for nonsmokers and 10 for smokers [91]. Severe

outcome was defined as pre-eclampsia associated with delivery before 34 weeks,

birth weight less than the 10th percentile associated with delivery before

34 weeks, fetal death, or placental abruption.

A multicenter study of 7851 women with singleton pregnancies in an

unselected population showed that the sensitivity of transvaginally obtained

uterine Doppler velocimetry with a PI of greater than 1.63 (95th percentile) at

23 weeks is 93.3% for predicting pre-eclampsia and fetal growth restriction

(FGR) and 56.3% for predicting FGR without pre-eclampsia when delivery

occurred before 32 weeks [92]. The negative predictive values were 100% and

Fig. 5. Demonstration of (A) normal uterine artery waveform and (B) uterine artery notching (arrow).


99.9%, respectively. When all deliveries were included, the sensitivity decreased

to 69% for prediction of pre-eclampsia and FGR and 13.2% for FGR without pre-

eclampsia. When the screening test was PI greater than 1.63 or the presence

of bilateral notches, the sensitivity for pre-eclampsia and FGR increased to 100%

and for FGR without pre-eclampsia to 68.8% in patients delivered before

32 weeks, although the screen-positive rate increased from 5.1% to 11.9%.

At this time, we are unable to alter the pathophysiology of the progres-

sive disease process that is first evidenced by abnormal uterine artery Doppler

velocimetry at 23 weeks. These fetuses may, however, benefit from closer

antepartum surveillance.

Summary

The first step in the management of the IUGR fetus is diagnosis. Fundal height

is the best screening tool, and ultrasound biometry is the best method for

detecting the small fetus. Doppler velocimetry is the most important means

of diagnosing the IUGR fetus who is at risk for adverse perinatal morbidity

and mortality.

It is difficult to determine the best time to deliver the IUGR fetus: one must

balance the risks of prematurity with the risks of further intrauterine de-

compensation. For the very preterm fetus, there may be some benefit to delaying

delivery until after venous evidence of circulatory decompensation is present,

but before the BPP becomes very abnormal. Two complicating factors in the

management of IUGR are its varied causes and the fact that not all IUGR fetuses

demonstrate the same patterns of decompensation. We need studies that compare


NST, BPP, and Doppler surveillance to one another and to management strategies

that combine them. Perhaps an integration of the testing modalities that reflect

central nervous system phenomena (NST, BPP) and circulatory phenomena

(Doppler velocimetry) will emerge as the best antepartum method of testing fetal

well-being.

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Diagnosis and management of intrauterine growth restriction