Clinical Expert Series
A Practical Approach to Fetal Growth Restriction Joshua A. Copel,
MD,
and Mert Ozan Bahtiyar,
MD
Fetal growth restriction is one of the most complex problems encountered by obstetricians. Ultrasound-estimated fetal weight less than the 10th percentile for the gestational age is the most widely accepted diagnostic criterion. Management protocols vary from institution to institution. Doppler velocimetry provides valuable information about fetal status. We offer a practical approach to management and timing of delivery based on available data in the literature. (Obstet Gynecol 2014;123:1057–69) DOI: 10.1097/AOG.0000000000000232
F
etal growth restriction is a complex problem from its diagnosis to prenatal management, and regarding optimal timing of delivery. It is synonymous with the term intrauterine growth restriction. Although there have been varying definitions of fetal growth restriction in the past, for the purposes of this review we used an estimated fetal weight less than the 10th percentile for gestational age as the definition.1 There is less consensus about how frequently to monitor these pregnancies (antenatal testing should be used for fetal monitoring) and when these fetuses should be delivered. In this article we present our approach to the management of patients with growth-restricted fetuses. Fetal growth restriction and small for gestational age (SGA) status are frequently used interchangeably in the literature and in daily clinical practice. Although fetal growth restriction is a prenatal definition, SGA describes postnatal status. The term “SGA” should be reserved to describe new-
From the Departments of Obstetrics, Gynecology, and Reproductive Sciences and Pediatrics, Yale University School of Medicine, New Haven, Connecticut. Continuing medical education for this article is available at http://links.lww. com/AOG/A490. Corresponding author: Mert Ozan Bahtiyar, MD, Department of Obstetrics, Gynecology and Reproductive Sciences, 333 Cedar Street, P.O. Box 8063, New Haven, CT 06520-8063; e-mail: mert.bahtiyar@yale.edu. Financial Disclosure The authors did not disclose any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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borns whose weight is less than or equal to the 10th percentile for gestational age at birth.1
BACKGROUND Fetal growth restriction is associated with increased perinatal mortality and morbidity. More severe growth restriction results in greater risk for worse perinatal outcome.2 The gestational age at which growth restriction is diagnosed is important from the neonatal outcome perspective. Among preterm newborns born at less than 37 weeks of gestation, there is no specific birth weight percentile at which morbidity and mortality rates increase. At term (37 weeks of gestation or later), neonatal mortality increases significantly among newborns with birth weight less than the third percentile (neonatal mortality50.3%) compared with normally grown newborns (neonatal mortality50.03%; P,.001).3 Neonates born at 32 to 42 weeks of gestation with a birth weight less than the 10th percentile for gestational age were four-times to six-times more likely to have cerebral palsy than were normally grown neonates.4 Available data suggest that in term fetuses an estimated fetal weight at or less than the third percentile would more accurately predict morbidity and mortality than would higher weight cutoffs. It remains clinically useful to use the estimated fetal weight at the 10th percentile threshold or less because of the inherent imprecision of ultrasound estimates of fetal weight to maintain a high detection rate of fetuses with true fetal growth restriction, although some normal fetuses will be misdiagnosed as having growth restriction.
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PREDICTION OF FETAL GROWTH RESTRICTION Affected Newborns Patterson et al5 followed-up 9,596 patients throughout two pregnancies; the overall fetal growth restriction rate in the first child was 12.4%. Among patients without any medical complications either in the first pregnancy or in the second pregnancy, the prevalence of recurrent fetal growth restriction was significantly related to the severity of growth restriction in the first pregnancy. If the birth weight of the first newborn was more than the 10th percentile, the risk of fetal growth restriction for the second newborn was 8.2%. If the birth weight was less than or equal to the 10th percentile for the first newborn, the risk of fetal growth restriction for the second newborn was significantly increased up to 20.1% (P,.001). The more severe the fetal growth restriction, the higher the risk of recurrence.
Serum Analytes Maternal serum analytes during the first and second trimesters can be reasonable predictors of fetal growth restriction later in pregnancy (Table 1). Pregnancyassociated plasma protein-A levels less than the first percentile (less than 0.29 multiples of the median) and pregnancy-associated plasma protein-A less than the 5th percentile (less than 0.45 multiples of the median),6,7 first trimester free b-hCG level less than the first percentile (less than 0.21 multiples of the
median),6 low unconjugated estriol (less than 0.5 multiples of the median) level in the second trimester,8 and unexplained increased maternal serum alphafetoprotein level (more than 2.0 multiples of the median) in the second trimester have been associated with low birth weight.9,10 In our institution, we recommend a fetal growth ultrasound examination at 32 weeks of gestation for pregnancies complicated with pregnancy-associated plasma protein-A less than the 2.5th percentile or unexplained increased maternal serum alphafetoprotein more than 2.0 multiples of the median. If the follow-up growth ultrasound scan is normal, with an estimated fetal weight more than the 10th percentile, we resume routine prenatal care (ie, we do not add any antepartum testing for normally grown fetuses).
Ultrasound Findings Single umbilical artery is the most common congenital abnormality of the umbilical cord. The prevalence of single umbilical artery ranges from 0.2% to 11%, depending on the population studied.11–15 Neonates with isolated single umbilical artery have increased rates of growth restriction (10.9% compared with 25.0%) and estimated fetal weight less than the 10th percentile (odds ratio 2.23; 95% confidence interval [CI] 1.84–2.69).16 In our institution, we recommend a fetal growth ultrasound examination at 32 weeks of gestation or pregnancies complicated with single umbilical artery. If the follow-up growth ultrasound scan is
Table 1. Diagnostic Performance of Maternal Serum Analytes During the First and Second Trimesters in Predicting Fetal Growth Restriction (Estimated Fetal Weight Less Than the 10th Percentile) Analyte First trimester PAPP-A Less than 5th percentile Less than 1st percentile Free b-hCG Less than 5th percentile Less than 1st percentile Second Trimester AFP More than 1.5 MoM More than 2.0 MoM uE3 Less than 0.5 MoM
OR
95% CI
Sensitivity
Specificity
PPV
NPV
2.74 3.53
2.16–2.81 2.74–4.55
10.4 2.9
95.4 99.2
18.7 26.3
91.3 91.0
0.8–2.0 0.8–2.0
5.1 5.1
95.8 95.8
7.4 7.4
93.8 93.8
1.41 1.65
1.07–1.87 1.28–2.12
19.6
90.4
3.9
98.3
1.79
1.79–2.44
1.3 1.3
OR, odds ratio; CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value; PAPP-A, pregnancy-associated plasma protein-A; AFP, alpha-fetoprotein; uE2, unconjugated estriol; MoM, multiples of the median. Data from Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, et al. Association of extreme first-trimester free human chorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. Am J Obstet Gynecol 2004;191:1452–8; Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstetrics Gynecol 2004;191:1446–51; and Dugoff L, Hobbins JC, Malone FD, Vidaver J, Sullivan L, Canick JA, et al. Quad screen as a predictor of adverse pregnancy outcome. Obstet Gynecol 2005;106:260–7.
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normal, with an estimated fetal weight more than the 10th percentile, we resume routine prenatal care. In a retrospective case control study, Heinonen17 showed that velamentous umbilical cord insertion was associated with higher risk of low birth weight (less than 2,500 g), SGA, preterm delivery, and low Apgar scores at 1 and 5 minutes. Marginal cord insertion, as shown by Liu et al,18 does not confer the same risk. As such, we recommend a fetal growth ultrasound examination at 32 weeks of gestation or for women with a previous diagnosis of a velamentous cord insertion but not a marginal insertion. If the follow-up growth ultrasound scan is normal, with an estimated fetal weight more than the 10th percentile, we resume routine prenatal care.
DIAGNOSIS A variety of tools are available for the diagnosis of fetal growth restriction. The simplest way of estimating fetal weight is based on clinical examination. Correlation between fundal height measurement in centimeters and gestational age is well-established in clinical practice and is a reasonable screening tool in low-risk and normal-weight women.19 Compared with ultrasonography, clinical estimation of birth weight is less accurate for fetuses weighing less than 2,500 g.20 The detection rate for fetal growth restriction based on clinical examination ranges from less than 35% to as high as 86%, whereas specificity is as high as 96%.19,21,22 Maternal obesity and uterine leiomyomas may limit the accuracy of fundal height measurement as a screening tool.1 In clinical practice, fundal height more than 4 cm less than expected for gestational age should indicate clinical suspicion for fetal growth restriction.
Fetal biometry is the cornerstone of the diagnosis of growth restriction. The most commonly used criterion to diagnose fetal growth restriction is an ultrasound-estimated fetal weight less than the 10th percentile for gestational age. This assumes that the pregnancy is dated accurately. Inaccurate dating (ie, overestimation of the actual length of gestation) may lead to a false diagnosis of fetal growth restriction. First-trimester crown rump measurement is the most accurate means for ultrasound dating of pregnancy. Later in pregnancy, biparietal diameter, abdominal circumference, and femoral diaphysis length can be used to estimate gestational age.23 Among other measurements, the transverse cerebellar measurement appears to provide a unique reference point because at 14 and 24 weeks of gestation the transverse diameter of the cerebellar hemispheres (in millimeters) is a close approximation of the gestational age in weeks.24,25 Cerebellar diameters can be used as an internal control when determining gestational age in the fetus with suspected fetal growth restriction because some studies have shown that cerebellar diameters are normal in neonates with fetal growth restriction.24 A pregnancy dated by clear early criteria should never be redated later in pregnancy based on smaller than expected fetal measurements. There are numerous formulas for estimating fetal weight, all with similar accuracy.26 Although estimated fetal weight less than the 10th percentile is one of the most commonly used criteria for diagnosis of fetal growth restriction, other absolute ultrasound measurements or calculated ratios have also been used to diagnose growth restriction (Table 2).27,28 In our practice, we use an estimated fetal weight less than the 10th percentile or abdominal circumference less
Table 2. Accuracy of Ultrasound Measurements in Detecting Fetal Growth Restriction Predictive Value27,28 Criterion Advanced placental grade Elevated FL/AC ratio Small BPD Small BPD and advanced placental grade Low EFW (less than 10th percentile) Decreased AFVs Elevated HC/AC ratio AC less than 10th percentile27,* AC less than 5th percentile39,*
Sensitivity
Specificity
Positive
Negative
62 34–49 24–88 59 89 24 82 62 98
64 78–83 62–94 86 88 98 94 91
16 18–20 21–44 32 45 55 62 67 37
94 92–93 92–98 95 92 98 90
FL, femur length; AC, abdominal circumference; BPD, biparietal diameter; EFW, estimated fetal weight; AFV, amniotic fluid volume; FL, femur length; AC, abdominal circumference; HC, head circumference; AC, abdominal circumference. Data are %. * Data derived from separate studies and are not directly comparable. Data from Dudley NJ. A systematic review of the ultrasound estimation of fetal weight. Ultrasound Obstet Gynecol 2005;25:80–9 and Ott WJ. Diagnosis of intrauterine growth restriction: comparison of ultrasound parameters. Am J Perinatol 2002;19:133–7.
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than the 5th percentile as the definition for fetal growth restriction. Although many constitutionally small fetuses will be classified as having growth restriction with this threshold, it is a reasonable point for initiating testing (vide infra) to avoid false-negative diagnoses. Fetuses with an abdominal wall defect pose a special dilemma in ultrasound estimation of the weight. Newborns with gastroschisis have higher rate of SGA, ranging from 23% to 52%.29–31 Ultrasonography overestimates fetal growth restriction in fetuses with gastroschisis, mainly because of the smaller abdominal circumference found in fetuses with significant amounts of bowel tissue outside the abdominal cavity.30,31
ETIOLOGY Fetal growth restriction is the final manifestation of a variety of different maternal, fetal, and placental conditions; the most common etiologies are listed in Box 1. A detailed discussion of etiologies for fetal growth restriction is out of the scope of this article. The breakdown of frequencies of the different etiologies is highly dependent on the patient population studied; therefore, precise statistics regarding relative frequencies of etiologies are not clinically helpful. Once the diagnosis of fetal growth restriction is established, one of the most important issues is to determine if the fetus in question is constitutionally small, a diagnosis of exclusion. Maternal history should be obtained and prenatal data including available aneuploidy screening or invasive testing results should be reviewed. Special attention should also be given to examining the fetus for any sign of congenital infections (ie, intracranial or hepatic calcifications, ventriculomegaly). The fetus should be examined for signs of congenital abnormalities and chromosomal anomalies. If congenital infections are suspected, maternal serum antibody titers should be tested, unless the patient is having an amniocentesis for aneuploidy. If amniocentesis is performed, in addition to fetal karyotype and comparative genomic hybridization, the amniotic fluid should be tested for cytomegalovirus and toxoplasmosis by polymerase chain reaction, which is a more sensitive and specific test than culture. Patients who decline invasive testing can be offered maternal plasma cell–free fetal DNA testing for aneuploidy screening, recognizing that the data obtained are limited to the common aneuploidies, and that other karyotype abnormalities will not be detected with current technology.32 In our institution, we recommend at least a fetal growth ultrasound scan at 32 weeks of gestation age for pregnancies with maternal and fetal risk factors. If the follow-up growth ultrasound test results are normal (estimated fetal weight more than the 10th percentile),
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Box 1. Risk Factors for Fetal Growth Restriction
Maternal Advanced maternal age Chronic medical diseases Hypertension Chronic hypertension Gestational hypertension Pregestational diabetes mellitus of advanced classes Renal disease Hyperthyroidism Hemoglobinopathies Autoimmune disease Systemic lupus erythematosus Cyanotic cardiac disease Antiphospholipid antibody syndrome Inadequate nutrition, malabsorption, and poor weight gain Medication exposure Phenytoin Valproic acid Trimethadione Warfarin Cyclophosphomide Substance abuse Tobacco Alcohol Cocaine Methamphetamines Narcotics
Fetal Multiple gestation Infection Rubella Cytomegalovirus Herpes Toxoplasmosis Malaria Syphilis Chagas disease Anomalies Chromosomal and genetic Trisomy 13 Trisomy 18 Congenital heart defects Gastroschisis
Placental Single umbilical artery Abnormal cord insertion Velamentous Bilobed or circumvallate placenta Small placenta Confined placental mosaicism Data from Fetal growth restriction. Practice Bulletin No. 134. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:1122–33 and modified from Copel JA, D’Alton ME, Grataco´s E, Platt LD, Tutschek B, Feltovich H, et al. Obstetric imaging. Philadelphia (PA): Elsevier Health Sciences; 2012.
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we resume routine prenatal care (ie, we do not add any antepartum testing for normally grown fetuses). In addition, for pregnancies with chronic maternal conditions that may affect fetal growth such as hypertension and diabetes, especially in obese gravid women, we perform monthly scans for growth surveillance.
FETAL ASSESSMENT Antepartum fetal testing methods may include fetal kick counts, nonstress tests, fetal biophysical profiles, and Doppler assessments and invasive tests, including amniocentesis or cordocentesis. The current literature suggests that there is no one ideal test for all growthrestricted fetuses.33 Daily fetal kick counts and once or twice weekly nonstress tests and biophysical profiles are essential basic tests that should be used in assessment of the well-being of those with fetal growth restriction. In our practice, we start antenatal testing as soon as fetal growth restriction diagnosis is established, with twiceweekly nonstress tests with amniotic fluid assessment (amniotic fluid index or maximum vertical pocket) or biophysical profile based on gestational age. We further supplement antenatal surveillance with once-weekly Doppler ultrasonography of umbilical artery. We add middle cerebral artery and ductus venosus Doppler assessment if there is an elevated systolic to diastolic velocity ratio or absent or if reverse-end-diastolic flow is found in the umbilical artery.
DOPPLER VELOCIMETRY Indices Doppler indices are used to assess fetal status. The most commonly used indices are the systolic to
diastolic velocity ratio, the pulsatility index, and the resistance index (Fig. 1). Advanced ultrasound machines are frequently equipped with automatic pattern recognition software for index calculation based on autotracing functionality. Although this function is often useful, in our experience it can sometimes be misleading. If the Doppler flow signal is weak, the software can have difficulty recognizing the pattern. When the autotrace does not closely track the visible flow velocity waveform, we recommend manual tracing for an accurate result. This is particularly an issue if there is minimal, absent, or reverse diastolic flow, when the autotracking function will be most inaccurate.
Umbilical Artery Doppler assessment of the umbilical artery is an essential portion of the evaluation of fetuses with growth restriction. A freely floating loop, portion, or segment, approximately at the mid portion of the umbilical cord, is identified. Attention should be given to ensure that the umbilical cord is not compressed between the extremities or against the uterine wall because this may affect the flow pattern by changing the vascular resistance because of external compression. Although we advocate using a free loop, it should be noted that umbilical artery blood flow can be assessed at any portion of the umbilical cord. However, operators should note that waveforms obtained near the placental end of the cord show higher end-diastolic flow velocity than waveforms obtained near the abdominal cord insertion. Although most of the indices are calculated ratios (ie, systolic to diastolic velocity ratio, resistance index,
Fig. 1. Measured and calculated Doppler ultrasonography indices. PSV, peak systolic velocity; EDV, end-diastolic velocity; RI, resistive index; PI, pulsatility index; S/D, systolic-to-diastolic ratio; TAPV, time-averaged peak velocity (used to calculate PI but not used as an individual measurement). Copel. Practical Approach to Fetal Growth Restriction. Obstet Gynecol 2014.
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pulsatility index) that do not require measurement of absolute flow velocities, the angle of insonation (angle between the ultrasound beam and the direction of flow in the interrogated vessel) should still be kept as low as possible (less than 30 degrees) during Doppler assessment to maximize the systolic and diastolic frequency shifts (Fig. 1). During a normal pregnancy, there is a progressive increase in end-diastolic velocity in the umbilical artery because of decreasing downstream impedance to flow as the placental vessels grow and branch. This causes all of the umbilical artery Doppler indices to become progressively lower across the third trimester (Fig. 2). In contrast, there is a progressive reduction of umbilical artery diastolic velocity because of increasing placental impedance in growth-restricted pregnancies at risk for stillbirth and asphyxia, which result in increases in all indices (Fig. 3). Current evidence suggests that the use of Doppler ultrasonography in high-risk pregnancies reduces the risk of perinatal deaths in fetal growth restriction fetuses while requiring fewer obstetric interventions.34 Routine fetal umbilical artery Doppler ultrasound examination in low-risk populations does not improve perinatal outcomes, including perinatal mortality, so it should not be performed in low-risk or in normally grown fetuses.35
Middle Cerebral Artery Correct technique is critical in determining the middle cerebral artery (MCA) Doppler velocity waveform. Excessive pressure to the fetal head through the ultrasound probe may also change the waveform, reducing apparent end-diastolic flow. The middle cerebral artery signal is obtained from an axial section of the brain, including the thalami and cavum septi pellicidi. The middle cerebral artery is examined as closely as possible to its origin. It does not matter whether the near or far side vessel is interrogated, as long as the angle between the ultrasound beam and the direction of blood flow is kept as close as possible to 0 degrees. The point of measurement is very important because the peak systolic velocity decreases as the sample volume is placed more distally in the vessel. (Fig. 4) The peak velocity and shape of the waveform become highly variable during fetal breathing, so episodes of fetal breathing should not be used (remembering that fetal breathing suggests good fetal condition as part of the biophysical profile). Middle cerebral artery Doppler is commonly used to assess suspected fetal anemia, based on peak systolic velocity, and to determine presence of “brain sparing” in fetal growth restriction. Increases in placental blood flow impedance and decreases in cerebral blood flow
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impedance lead to “brain sparing,” which is associated with an increase in middle cerebral artery diastolic flow velocities. These changes in blood flow patterns in growth-restricted fetuses with brain sparing lead to a decrease in the Doppler cerebro-placental ratio,36 defined as cerebral resistance index divided by umbilical artery resistance index.37 A similar relationship can be seen with the systolic to diastolic velocity ratio and the pulsatility index.38
Ductus Venosus The ductus venosus is a small vessel connecting the intra-abdominal umbilical vein with the inferior vena cava. The ductus venosus may be identified in different planes. The most common approaches are the sagittal or oblique parasagittal views or the cross-sectional (axial) abdominal view. In sagittal views, the umbilical cord insertion into the abdomen is first identified. The umbilical arteries travel caudally, whereas the umbilical vein initially travels cephalad and follows the liver contour, then turns sharply posteriorly toward the inferior vena cava. The ductus venosus arises from the apex of the umbilical vein, where it is traveling posteriorly, and is directed toward the insertion of the inferior vena cava and the right atrium. Because of fetal positioning, it may not be possible to obtain the ductus venosus signal in sagittal views. The ductus venosus can also be identified with color Doppler in a cross-sectional view of the abdomen at the level of the stomach. However, in this approach, visual confirmation of the continuity between the ductus venosus and the inferior vena cava and right atrium is not possible, so the operator must rely on the characteristic ductus venosus blood flow pattern. The ductus venosus normally has a triphasic blood flow pattern, with persistent forward flow throughout the cardiac cycle. Because there is no intervening valvular structure, the ductus venosus flow pattern directly reflects pressure changes within the right atrium. The hepatic vein and inferior vena cava, which are in close proximity, have biphasic blood flow patterns. However, normally, blood flows retrograde during end-diastole in the hepatic vein and inferior vena cava, which would be an abnormal finding for the ductus venosus. The ductus venosus also has much higher absolute velocities than are typically seen in other veins (Fig. 5). As for all fetal Doppler, the ductus venosus signal should be obtained during fetal rest and in the absence of fetal breathing movements. Because there is no intravascular valvular structure at the ductus venosus– inferior vena cava junction, changes in intrathoracic pressures are directly reflected in ductus venosus flow patterns.
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Fig. 2. Changes in umbilical artery flow pattern during uncomplicated pregnancy. A. At 21 weeks of gestation. B. At 28 weeks of gestation. C. At 30 weeks of gestation. PSV, peak systolic velocity; EDV, end-diastolic velocity; RI, resistive index; PI, pulsatility index; S/D, systolic-todiastolic ratio; TAPV, time-averaged peak velocity (used to calculate PI but not used as an individual measurement). Copel. Practical Approach to Fetal Growth Restriction. Obstet Gynecol 2014.
Growth-restricted fetuses with absent or reverse ductus venosus flow during atrial systole (“a wave�) have worse perinatal outcomes. Absent or reverse flow during atrial systole in the ductus venosus suggests
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a high risk of fetal death within 1 week. The incidence of ductus venosus reverse a-wave in fetuses with intact survival is much lower than in those with stillbirth (3.2% compared with 61.1%; P,.005). Ductus venosus
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reverse a-wave for more than 7 days predicts stillbirth with 100% sensitivity and 80% specificity (likelihood ratio55.0; P,.001). In the majority of fetuses with fetal growth restriction, sequential deterioration of venous flow precedes biophysical profile score deterioration (see Temporal Change in Doppler).
Uterine Artery Uterine artery Doppler reflects flow impedance in the utero-placental circulation, which decreases with gestation. The initial decline until 24 to 26 weeks of gestation is thought to be attributable to trophoblastic invasion of the spiral arteries, but a continuing decline in impedance may be explained in part by a persisting hormonal effect on elasticity of arterial walls. Impedance in the uterine artery on the same side as the placenta is lower than on the contralateral side. We do not recommend routine utilization of uterine artery Doppler study for prenatal assessment of fetal growth restriction fetuses because, although uterine artery Doppler reflects flow impedance in the utero-placental circulation, measurement has not been proven to reduce perinatal morbidity or mortality.
TEMPORAL CHANGES IN FETAL DOPPLER Doppler changes precede deteriorating biophysical profile scores in fetuses with severe intrauterine growth restriction.39,40 These changes predominantly occur during the week before delivery. The umbilical artery and ductus venosus Doppler changes occur approximately 4 days before biophysical profile deterioration. At 2 to 3 days before delivery, fetal breathing movement begins to diminish. Within 24 hours, amniotic fluid volume begins to decrease. The composite biophysical profile score decreases abruptly on the day of delivery, with loss of fetal movement and tone. In our practice, frequent serial longitudinal antenatal testing with biophysical profile or nonstress test and Doppler velocimetry allow us to risk-stratify our patients. We monitor fetuses with fetal growth restriction with normal biophysical profile and Doppler velocimetry as outpatients. Once absent or reverse end-diastolic blood flow is noted in the umbilical artery, the patients are admitted to the hospital for closer monitoring. We do not deliver newborns solely based on Doppler abnormalities except absent
Fig. 3. Progressive worsening of the umbilical artery Doppler pattern. A. Normal blood flow pattern. B. Increased systolic-to-diastolic (S/D) ratio. C. Absent enddiastolic blood flow. D. Reverse end-diastolic blood flow. PSV, peak systolic velocity; EDV, end-diastolic velocity;
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MDV, minimum diastolic velocity; RI, resistive index; PI, pulsatility index; TAPV, time-averaged peak velocity (used to calculate PI but not used as an individual measurement). Copel. Practical Approach to Fetal Growth Restriction. Obstet Gynecol 2014.
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Fig. 4. Middle cerebral artery (MCA) Doppler assessment. The MCA peak systolic velocity can be used to assess fetuses at risk for anemia. MCA pulsatility index can be used to assess “brain sparing.” PSV, peak systolic velocity; EDV, end-diastolic velocity; MDV, minimum diastolic velocity; RI, resistive index; PI, pulsatility index; S/D, systolic-to-diastolic ratio; TAPV, timeaveraged peak velocity (used to calculate PI but not used as an individual measurement). Copel. Practical Approach to Fetal Growth Restriction. Obstet Gynecol 2014.
or reverse a-wave in the ductus venosus; even then, decisions must be made in conjunction with the parents and with added counseling from neonatologists regarding expected outcomes and after administration of corticosteroids for enhanced fetal maturation when appropriate.
MANAGEMENT In a multinational prospective randomized study, the Growth Restriction Intervention Trial (GRIT), immediate compared with deferred delivery of fetuses with fetal growth restriction was compared at ages 2 years and 9 years. In this study, women with fetal growth
restriction between 24 and 36 completed gestational weeks, with an umbilical artery Doppler waveform that had been recorded, and with the responsible clinician uncertain whether to deliver the neonate immediately were randomly allocated to either “deliver now” or “defer delivery” groups until the decision could not be safely delayed. The GRIT investigators found little difference in overall mortality or 2-year outcomes associated with immediate or deferred delivery. At 9 years, there was still no difference between groups regarding numbers of deaths, rate of severe disability or in the mean cognition scores motor scores, and parentassessed behavior scores.
Fig. 5. Ductus venosus Doppler assessment. Hepatic vein, ductus venosus, and inferior vena cava merge immediately before draining into the right atrium. Copel. Practical Approach to Fetal Growth Restriction. Obstet Gynecol 2014.
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Biophysical profile is one of the most common tests used to assess fetal well-being.41 A normal biophysical profile is associated with a decreased rate of fetal death within 1 week of testing.42 Despite its frequent use, biophysical profiles alone have not been reliable in premature neonates (before 32 weeks of gestation) weighing less than 1,000 g because of high rates of false-positive and negative results.43 Decisionanalysis models showed that when compared with the no-testing strategy, the biophysical profile–only scheme was associated with a 60% reduction in fetal death, a 59% reduction in neonatal death, and a 92% reduction in neonatal disability.44 Umbilical artery Doppler ultrasound assessment of high-risk pregnancies has been shown to be associated with a reduction in perinatal deaths (risk ratio 0.71; 95% CI 0.52–0.98), inductions of labor (average risk ratio 0.89; 95% CI 0.80–0.99), and cesarean deliveries (risk ratio 0.90, 95% CI 0.84–0.97).45 More recently, Berkley et al46 proposed a management algorithm for pregnancies complicated with fetal growth restriction that incorporates Doppler ultrasound findings in the umbilical artery (Fig. 6). Briefly, in this algorithm, pregnancies involving fetal growth restriction are monitored with weekly umbilical artery Doppler evaluation. Delivery was recommended after 37, 34, and 32 gestational weeks age if there was elevated systolic-to-diastolic ratio, absent end-diastolic blood flow, or reverse end-diastolic blood flow, respectively.
Regarding available data, we suggest the following management option.
Initial Diagnosis • Establish gestational age as reliably as possible. • Diagnosis of fetal growth restriction requires estimated fetal weight less than the 10th percentile, abdominal circumference less than the 5th percentile, or both. • Obtain detailed maternal history. • Review prenatal records. • Reassess fetal anatomy. • Reassess fetus for signs of congenital infections. • For periviable fetuses, consider outcome from calculator found at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Extremely Preterm Birth Outcome Data (http://www.nichd.nih.gov/ about/org/der/branches/ppb/programs/epbo/Pages/ epbo_case.aspx?start502:39:03).
Prenatal Monitoring • In our practice, we start antenatal testing as soon as fetal growth restriction diagnosis is established, with twice-weekly nonstress tests with amniotic fluid assessment (amniotic fluid index or maximum vertical pocket) or biophysical profile based on gestational age.
Fig. 6. Management recommendation for fetal growth restriction incorporating Doppler velocimetry. aIn conjunction with antepartum testing. IUGR, intrauterine growth restriction; UA, uterine artery. Reprinted from Berkley E, Chauhan SP, Abuhamad A. Doppler assessment of the fetus with intrauterine growth restriction. AJOG 2012;206:300–8. Copyright 2012, with permission from Elsevier. Copel. Practical Approach to Fetal Growth Restriction. Obstet Gynecol 2014.
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• Once per week we perform Doppler ultrasonography of the umbilical artery. We add middle cerebral artery and ductus venosus Doppler assessments if increased systolic-to-diastolic velocity ratio or absent or reverse end-diastolic flow in umbilical artery is noted. • Admit patient to the hospital for close monitoring if absent or reverse end-diastolic velocities are present in the umbilical artery. • Follow-up fetal growth with ultrasonography every 2 weeks.
Admission (Inpatient Management) • Consider admission to the hospital if absent or reverse end-diastolic velocities are present in the umbilical artery and if the fetus is viable. • Administer corticosteroids for fetal lung maturity if admission occurs before 34 weeks of gestation. • Perform fetal monitoring (nonstress tests) every 8 hours or more frequently as indicated and perform biophysical profile daily or more often as indicated. • Delivery for decline in biophysical profile score less than six out of eight, nonreassuring fetal heart rate tracing, or inadequate interval growth over the course of 14 days, or a combination of these.
Delivery • Term (37 0/7 weeks of gestation or more) B Deliver if estimated fetal weight is less than the 5th percentile, or oligohydramnios with estimated fetal weight less than the 10th percentile, or worsening antenatal testing results. B Otherwise, delay delivery as long as antenatal testing is reassuring. B Plan elective delivery after 39 weeks of gestation. B Induction of labor can be attempted depending on the indication for delivery. B We reserve cesarean delivery for obstetric indications. • Preterm (before 37 weeks of gestation) B It is not possible to make absolute recommendation on timing unless other antenatal testing is reassuring based on GRIT data. B Monitor fetal growth every 2 weeks. B Consider delivery if no growth occurs over the course of 14 days. B Delivery should be considered for worsening antenatal testing (biophysical profile score less than six out of eight or nonreassuring fetal heart rate tracing).
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B
When preterm delivery before 32 weeks of gestation is imminent, consider intravenous magnesium sulfate administration for fetal neuroprotection.47 “When delivery for fetal growth restriction is anticipated before 34 weeks of gestation, the delivery should be planned at a center with a neonatal intensive care unit.”1
POSTNATAL OUTCOME The interaction between fetal genetic make-up and in utero environment influences the susceptibility to certain disorders later in life. Fetal growth restriction is associated with increased susceptibility to diabetes and cardiovascular disease in adulthood.48 Gestational age at the time of delivery appears to be a major factor in cognitive outcomes among fetuses with fetal growth restriction. For SGA newborns delivered after 28 weeks of gestation, abnormal prenatal umbilical artery Doppler findings were not associated with lower developmental scores at corrected ages of 3 years and 6 years.49 Neonates born before 29 weeks of gestation with fetal growth restriction and absent or reverse enddiastolic flow in the umbilical artery had an increased risk for cognitive impairment at an early age (5–8 years of age) compared with those delivered preterm for other reasons. Differences in cognitive outcome were restricted to boys.50
CONCLUSION Fetal growth restriction is a complex disorder. Estimated fetal weight less than the 10th percentile or abdominal circumference less than the 5th percentile, or both, have good sensitivity. Diagnosis of fetal growth restriction can only be made reliably if the gestational age is determined reliably. Multiple etiologies should be considered, including maternal, fetal, and placental. Antenatal testing with fetal heart rate monitoring, biophysical profile, and Doppler assessment should be used in combination to assess fetal status. Once antenatal testing and Doppler assessment results are abnormal, timely delivery is indicated. Umbilical artery Doppler changes alone do not necessitate delivery, especially in preterm fetuses. Planned premature delivery should always be weighed against complications of prematurity, and antenatal corticosteroids should be used whenever time permits for anticipated deliveries before 34 weeks of gestation. Delivery should be delayed as safely as possible in pregnancies remote from term.
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