The diagnosis and management of intrauterine growth restriction is difficult. Perinatal mortality and morbidity worsen as the fetal weight declines. The 10th percentile has been used to define "small for gestational age" at all gestational ages. This approach assumes that the risk of perinatal mortality is the same at all gestational ages. Boulet et al1 have shown that this is, in fact, not the case. The risk of neonatal death at the 10th percentile has a bimodal distribution with peaks at 26 and 34 weeks' gestation. Hence, the 10th percentile is associated with an increased, but variable, risk of subsequent neonatal mortality. There is an acceleration in mortality and neonatal complications as the fetal weight falls below the 5th percentile2.
The first step in the appropriate management of small-for-gestational age fetuses is to delineate those fetuses who are truly at risk. An individual fetus' growth potential may be compromised, resulting in any or all of the neonatal complications of intrauterine growth restriction (IUGR) above the arbitrary 10th percentile cut-off. Customized standards for fetal growth are better able to distinguish between "physiologically small" and "pathologically small" fetuses3.
Serial abdominal circumference or fetal weight estimates are the best screening tests for IUGR4. Doppler studies are the mainstay for diagnosis and management. Complicated cases of early onset IUGR (< 30 weeks' gestation) may require a multi-vessel Doppler approach to evaluate pre-load, as well as after-load, affects of severe intrauterine growth restriction.
Placental studies have shown that > 60% of the placental vascular bed is obliterated once impedance is increased in the umbilical artery5. When there is absent diastolic flow in the umbilical artery, the capillaries in placental terminal villi are decreased in number and they have fewer branches6. Blood gases obtained at cordocentesis have shown that 80% of fetuses with absent diastolic flow are hypoxic and 46% are acidemic7. Absent end-diastolic flow and reversed diastolic flow within in the umbilical artery have an associated 40% and 70% perinatal mortality, respectively8.
A meta-analysis of nine randomized trials confirmed that perinatal mortality is significantly reduced when umbilical artery Doppler is used as an adjunct to fetal heart monitoring to manage IUGR9,10. The progressive waveform patterns associated with increasingly severe IUGR are illustrated in Figure 1a-d. Absent end-diastolic flow in the umbilical artery and middle cerebral artery pulsatility index < 5th percentile are considered "early" stage changes of IUGR. These Doppler alterations generally occur 14 days from delivery11, but may persist for up to 26 days prior to delivery12.
Fig 1a. Umbilical artery: normal S/D ratio. Click for larger image.
Fig 1b. Umbilical artery: elevated S/D ratio. Click for larger image.
Fig 1c. Umbilical artery: absent diastolic flow. Click for larger image.
Fig 1d. Umbilical artery: reversed diastolic flow. Click for larger image.
Screening a low-risk population with umbilical artery Dopplers does not reduce perinatal morbidity and mortality13 and is not recommended14.
Middle Cerebral Artery
With fetal hypoxemia, there is increased blood flow to vital organs (brain and myocardium) and reduced flow to the gastrointestinal tract and kidneys. Cerebral vasodilatation (Fig. 2a) is limited. The nadir of the middle cerebral artery PI is reached 14 days or more before fetal compromise15. With the onset of hypercapnia, vascular dilatation is suppressed by cerebral edema, resulting in a "normalization" of the middle cerebral artery pulsatility index (Fig. 2b)16. The reversal of adaptation in a growth restricted fetus is considered a poor prognostic sign. The middle cerebral artery peak systolic velocity becomes elevated (Fig. 2c) as a late finding in severe IUGR prior to a non-reassuring heart rate tracing, i.e. continuous late decelerations or a biophysical profile score < 417, 18. The increase in the middle cerebral artery peak systolic velocity is due to an elevated left cardiac output associated with increased placental vascular resistance18.
Fig 2a. Middle cerebral artery: pulsatility index < 5th percentile indicating brain-sparing. Click for larger image.
Fig 2b. Brain, middle cerebral artery: reversed diastolic flow. Click for larger image.
Fig 2c. Middle cerebral artery: elevated peak systolic velocity in growth restricted fetus at 26 weeks' gestation. Click for larger image.
Delivery should be considered when there is a 20-30% increase in the middle cerebral artery pulsatility index per day for 2 days (trend towards normalization)19. Since changes in the middle cerebral artery pulsatility index may occur daily, some of the changes noted above may be missed in an individual case. Because of the wide variability in middle cerebral artery indices, a single operator will have better and more consistent results20.
Intrauterine Growth Restriction with Normal Umbilical Artery Dopplers
Small fetuses with normal umbilical artery Dopplers have traditionally been considered constitutionally small. More recent data indicates that this category contains some fetuses with true growth restriction and subsequent abnormal childhood neurodevelopmental testing21. While the causes for IUGR with normal umbilical artery Dopplers may be heterogeneous, uteroplacental insufficiency is the etiology in the majority of cases.
A decreased pulsatility index in the middle cerebral artery indicates fetal adaptation, even in the presence of a normal umbilical artery Doppler. Hence, an abnormal umbilical artery waveform pattern is not universally the first Doppler sign of intrauterine growth restriction22. Growth restricted fetuses with a normal umbilical artery Doppler may have microstructural and metabolic brain changes consistent with abnormal intrauterine brain development. The maturation and myelination of the frontal areas of the brain occur later in development and they are, therefore, more vulnerable to mild degrees of hypoxia21. The frontal lobes are the area of the brain most affected by adverse neurological outcome in growth restricted fetuses23. A subgroup of intrauterine growth restricted fetuses with normal umbilical artery and normal middle cerebral artery Dopplers have frontal lobe vasodilatation as manifested by changes in the anterior cerebral artery24. Long-term studies of growth restricted fetuses have documented a deficiency in general cognitive competence, suggesting frontal lobe dysfunction25,26.
Once the pulsatility index in the middle cerebral artery is reduced, indicating increased diastolic flow, there is already a progressive reduction in blood flow to the frontal area. Perfusion of the basal ganglia continues to increase as the severity of intrauterine growth restriction increases. The regional redistribution of blood flow to the brain is dependent upon the severity and duration of the hypoxic insult25. Hence, "brain sparing" as documented by a middle cerebral artery pulsatility index < 5th percentile is not an entirely protective mechanism27.
The average shunting of blood through the ductus venosus normally decreases from 30% at 18-20 weeks to 18% at 31-34 weeks gestation28. The normal ductus venosus waveform pattern has a peak systolic, a peak diastolic and peak atrial velocity (Fig. 3a). The ductus venosus is the only venous vessel with forward flow during all phases of the cardiac cycle. The S-wave reflects the pressure gradient between the peripheral venous system and the right atrium. The D-wave represents the opening of the atrial ventricular valves and passive early filling of the ventricles. Between the S and the D wave is a period of isovolumetric relaxation (IVR) when atrial pressure and waning systolic ejection pressure are comparable. With increasing myocardial hypoxia and acidosis, the cardiac muscle is less compliant and isovolumetric relaxation decreases, may become absent (Fig.3b), or even reversed. An evaluation of IVR and the A-wave is a more accurate predictor of fetal outcome then noting the absence or reversal of the A-wave29.
Fig 3a. Ductus venosus: normal pulsatility index (0.64). Click for larger image.
Fig 3b. Ductus venosus: elevated pulsatility index (1.02). Click for larger image.
The pulsatility index is utilized to quantitate ductus venosus flow. With advancing gestation cardiac compliance increases and placental resistance falls. As a result, the pulsatility index of the ductus venosus normally declines with advancing gestation30. An increase in cardiac after-load or decreased cardiac compliance will result in a decrease in forward flow and an increase in the pulsatility index (Fig. 3c).
Fig 3c. Ductus venosus: absent IVR and reversed a-wave (a) flow. Click for larger image.
With hypoxemia there is an increase in umbilical venous flow through the ductus venosus and a reduction in hepatic blood flow31. Normal ductal flow suggests continued fetal compensation. Bellotti et al32 have documented an 80% change in ductal diameter during prolonged observations of two growth restricted fetuses. With further fetal deterioration, there is reversed flow during the atrial contraction of the ductus venosus and a markedly increased pulsatility index (Fig. 3d). This indicates a failure of compensatory mechanisms and the onset of right heart failure. Fetuses with reverse flow in the A-wave of the ductus venosus are not necessarily acidemic33, and may survive for days to weeks in utero34. Hence, the main goal of antepartum surveillance, when the gestation age is < 30 weeks, is to differentiate fetuses with ductal venosus reversed flow who require intervention from those whose delivery can be delayed from days to weeks.
Fig 3d. Ductus venosus: reversed a-wave. Click for larger image.
As with all Doppler waveform patterns, there is a transitional phase of ductus venosus reversed flow. Intermittent reversed flow in the ductus venosus may occur from 2 to 57 days. Once reverse flow is constant, it may persist from 1 to 23 days before delivery is mandated by non-reassuring fetal testing35.
Umbilical vein pulsations have been defined as a diastolic decrease in velocity of = 15% of baseline (Fig. 4).
Fig 4. Umbilical vein pulsation (arrow). Click for larger image.
Wave propagation from the ductus venosus to the umbilical vein is significantly reduced due to reflection at the inlet of the ductus. With distension of the ductus venosus due to hypoxia, the close approximation of the diameters between the ductus venosus and umbilical vein leads to less wave reflection, the transmission of the ductal wave to the umbilical vein, and umbilical venous pulsations36.
Pulsations in the umbilical vein are more common at the abdominal inlet than in a free-loop of umbilical cord or intra-abdominally. The constriction at the umbilical ring reduces the compliance of the vessel and, therefore, permits transmission of a pulse. The umbilical artery at the abdominal inlet may also transmit a pulse to the umbilical vein37.
The significance of umbilical vein pulsations relates primarily to its presence or absence in a free-loop of umbilical cord38. A single, double or triphasic umbilical vein pattern has been described. A single umbilical venous pulsation, possibly secondary to high resistance within the umbilical artery, is associated with a 15.8% perinatal mortality38. With increased hypoxia/hypercapnia, the ductal S and D wave may be reflected in the umbilical vein. An umbilical venous double pulsation is associated with a 61.5% perinatal mortality38. Finally, reversed flow in the A-wave may give rise to a triphasic umbilical venous pattern with systolic and diastolic antegrade flow and atrial reversed flow. This latter, rare umbilical venous pattern indicates right-sided cardiac compromise and a worsening fetal condition that results in fetal demise within 2-7 days and a high perinatal mortality even with expeditious delivery39,40.
Timing of Delivery
Until 26 weeks' gestation the primary contributor to neonatal outcome is gestational age20. After 27 weeks' gestation fetal acidemia and the risk of stillbirth must also taken into consideration when timing delivery.
A growth restricted fetus in the late 2nd and early 3rd trimester who has undergone chronic starvation may be able to tolerate continued stress better than a 3rd trimester fetus with a high metabolic demand who suddenly has a significant reduction in placental function.
When Doppler abnormalities develop at an early gestational age, it generally progresses more rapidly. With mild Doppler abnormalities, only the umbilical artery and middle cerebral artery are affected. If these initial Doppler abnormalities do not worsen within 7-10 days, they are unlikely to do so. Progressive placental dysfunction typically follows a sequence (Table I). The progression in severity of Doppler abnormalities within 2 weeks of detection indicate significant disease with early intervention likely41. In cases of pre-eclampsia, the Doppler changes are unpredictable34.
Table I. Typical progression of multi-vessel Doppler studies with progressive placental dysfunction
- Elevated umbilical artery S/D ratio
- Middle cerebral artery PI < 5th percentile (brain-sparing)
- Umbilical artery - absent diastolic flow
- Umbilical artery - reversed diastolic flow
- Ductus venosus - elevated pulsatility index
- Ductus venosus - reversed a-wave
- Ductus venosus - decreased IVR, reversed a-wave
- Umbilical vein double pulsations
- Umbilical vein triple pulsation with reversed a-wave flow
The combination of a multi-vessel Doppler study and biophysical profile are complimentary tests to assess acid base status and the timing of delivery42.
The American College of Obstetricians and Gynecologists recommends weekly fetal assessment (biophysical profile score, modified biophysical profile [non-stress test and amniotic fluid index] and umbilical Doppler velocimetry) in cases of intrauterine growth restriction43.
These recommendations must be modified depending upon gestational age and the severity of growth restriction.
The further a compromised vein is from the heart, the higher the perinatal mortality risk. For example, perinatal mortality is 8 times greater with an abnormal ductus venosus waveform pattern and 18 times greater with pulsations in the umbilical vein44. In fetuses with a gestational age < 30 weeks and an increased pulsatility in the ductus venosus, daily testing is appropriate. Absent or reversed ductus venosus A-wave, a reduced ductus venosus IVR, and a double pulsation in the umbilical vein of a free-loop of umbilical cord indicate fetal decompensation and mandates delivery at a tertiary center45.
In 70% of cases Doppler deterioration occurs 24 hours before a decline in the biophysical profile score. When both a multi-vessel Doppler study and the biophysical profile score are abnormal, an expeditious delivery is mandatory44.
Serial fetal biometry and multi-vessel Doppler studies are currently employed in an attempt to optimize neonatal survival. The complexity of the interaction between gestational age, fetal reserve, Doppler studies, and long-term neurobehavioral outcome, mandates that each case be assessed individually.
- Boulet SL, Alexander GR, Saliha HM, Kirby RS, Carol WA. Fetal growth risk curves: defining levels of fetal growth restriction by neonatal death risk. Am J Obstet Gynecol 2006;145:1571-1577.
- Scott K, Usher R. Fetal malnutrition: Its causes and effects. Am J Obstet Gynecol 1966;94:951-963.
- Figueras F, Gardosi J. Intrauterine growth restriction: new concepts in antenatal surveillance, diagnosis and management. Am J Obstet Gynecol 2011;204:288-300.
- Chang TC, Robson SC, Boys RC, Spencer JA. Prediction of the small for gestational age infants: which ultrasonic measurement is best? Obstet Gynecol 1992;80:1030-1038.
- Giles WB, Trudinger BJ, Baird PJ. Fetal umbilical artery flow velocity waveforms and placental resistance: pathological correlation Br J Obstet Gynaecol 1985;92:31-38.
- Krebs C, Macara LM, Leiser R, Bowman AW, Greer IA, Kingdom JCP. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstet Gynecol 1996;175:1534-1542.
- Nicolaides KH, Bilardo CM, Southill PW, Campbell S. Absence of end-diastolic frequencies in the umbilical artery: a sign of fetal hypoxia and acidosis. Br Med J 1988;297:1026-1027.
- Karsdorp VH, vanVugt JM, vanGreijn HP, Kostense PJ, Arduini D, Mantenegro N, Todros T. Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery. Lancet 1994;170:796-801.
- Alfiravic Z, Neilson JP. The current status of Doppler sonography in obstetrics. Curr Opin Obstet Gynecol 1996;8:114-118.
- Westergaard HB, Langhoff-Roos J, Lingman G, Marsál K, Kreiner S. A critical appraisal of the use of umbilical artery Doppler ultrasound in high-risk pregnancies: use of meta-analysis in evidence-based obstetrics. Ultrasound Obstet Gynecol 2001;17:466-476.
- Ferrzaai E, Bozzo M, Rigaro S, Bellotti M, Morabito A, Pardi G, Battaglia FC, Galan HL. Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth restricted fetus. Ultrasound Obstet Gynecol 2002;19:140-146.
- Foruzan I. Absence of end-diastolic flow velocity in the umbilical artery: a review. Obstet Gynecol Surv 1995;50:219-227.
- Bricker K, Leilson JP. Routine Doppler in ultrasound in pregnancy. Cochrane Database Syst Rev 2000; CD00:1450.
- Coomarasamy A, Fisk NM, Gee H, Robson SC. The investigation and management of the small-for-gestational-age fetus. Royal College of Obstetricians and Gynaecologists. Guideline No. 31, Nov 2002.
- Arduini D, Rizzo G, Romanini C. Changes of pulsatility index from fetal vessel preceding the onset of late decelerations in growth retarded fetuses. Obstet Gynecol 1992;79:605-610.
- Vyas S, Nicolaides KH, Bower S, Campbell S. Middle cerebral artery flow velocity waveforms in fetal hypoxemia. Br J Obstet Gynaecol 1990;97:797-803.
- Hanif F, Drennan K, Mari G. Variables that affect the middle cerebral artery peak systolic velocity in fetuses with anemia and intrauterine growth restriction. Am J Perinatol 2007;24:501-506.
- Mari G, Hanif F, Kruger M, Cosmi E, Santolaya-Forgas J, Treadwell MC. Middle cerebral artery peak systolic velocity: a new Doppler parameter in the assessment of growth restricted fetuses. Ultrasound Obstet Gynecol 2007;29:310-316.
- Konje JC, Bell SC, Taylor DJ. Abnormal Doppler velocimetry and blood flow volume in the middle cerebral artery in very severe intrauterine growth restriction: is the occurrence of reversal of compensation flow too late? Br J Obstet Gynaecol 2001;108:973-979.
- Baschat AA, Cosmi E, Bilardo CM, Wolf H, Berg C, Rigano S, Germer U, Moyano D, Turan S, Hartung J, Bhide A, Muller T, Bower S, Nicolaides KH, Thilaganathan B, Gembruch U, Ferrazzi E, Hercher K, Galan HL, Harman CR. Predictors of neonatal outcome in early onset placental dysfunction. Obstet Gynecol 2007;109:253-261.
- Cruz-Martinez R, Figueras F, Oros D, Padilla N, Melen E, Hernandez-Andrade E, Gratacos E. Cerebral blood perfusion and neurobehavioral performance in full-term small-for-gestational age fetuses. Am J Obstet Gynecol 2009;201:474e.1-7.
- Severi Fm, Bocchi C, Visentin A, Falco P, Cobelli L, Florio, P, Zagonari S, Pilu G. Uterine and fetal cerebral Doppler predict the outcome of third-trimester small-for-gestational age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2002;19:225-228.
- Sanz-Cortés M, Figueras F, Bargalló N, Padilla N, Amat-Roldan I, Gratacós E. Abnormal brain microstructure and metabolism in small-for-gestational age term fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2010;36:159-165.
- Benavides-Serralde JA, Hernández-Andrade E, Bello-Manoz JC, Figueroa-Diesel H, Gratacos E. Early changes in the anterior cerebral artery with respect to the middle cerebral artery in intrauterine growth restricted fetuses. Ultrasound Obstet Gynecol 2002;30:524.
- Hernandez-Andrade E, Figueroa-Diesel H, Jansson T, Rangel-Nava H, Gratacos E. Changes in regional fetal cerebral blood flow perfusion in relation to hemodynamic deterioration in severely growth-restricted fetuses. Ultrasound Obstet Gynecol 2008;32:71-76.
- Figueras F, Eixarch E, Meler E, Iraola A, Figueras J, Puerto B, Gratacos E. Small-for-gestational age fetuses with normal umbilical artery Doppler have suboptimal perinatal and neurodevelopmental outcome. Eur J Obstet Gynecol Reprod Biol 2008;136:34-38.
- Eixarch E, Meler E, Iraola A, Illa M, Crispi F, Hernandez-Andrade E, Gratacos E, Figueras F. Neurodevelopmental outcomes in 2-year-old infants who were small-for-gestational age term fetuses with cerebral blood flow redistribution. Ultrasound Obstet Gynecol 2008;32:894-899.
- Kiserud T, Rasmussen S, Skulstad S. Blood flow and degree of shunting through the ductus venosus in the human fetus. Am J Obstet Gynecol 2000;182:147-153.
- Picconi JL, Kruger M, Mari G. Ductus venosus s-wave/isovolumetric a-wave (SIA) index and A-wave reversed flow in severely premature growth-restricted fetuses. J Ultrasound Med 2008;27:1283-1289.
- Baschat AA. Ductus venosus Doppler for fetal surveillance in high-risk pregnancies. Clin Obstet Gynecol 2010;53:858-868.
- Kiserud T, Stratford L, Hanson MA. Umbilical flow distribution to the liver and the ductus venosus: an in vitro investigation of the fluid dynamic mechanism in the fetal sheep. Am J Obstet Gynecol 1997;177:86-90.
- Bellotti M, Pennati G, Pardi G, Fumero R. Dilatation of the ductus venosus in human fetuses: ultrasonographic evidence and mathematical modeling. Am J Physiol 1998;275 (Heart Circ Physiol 44):H1759-H1767.
- Picconi J, Hanif F, Mari G. Ductus venosus reversed flow in IUGR fetuses: Is it an indication for delivery? Am J Perinatol 2008;25:199-204.
- Mari G, Picconi J. Doppler vascular changes in intrauterine growth restriction. Semin Perinatol 2008;32:182-189.
- Picconi JL, Harif F, Drennan K, Mari G. The transitional phase of ductus venosus reversed flow in severely premature IUGR fetuses. Am J Perinatal 2008;25:199-203.
- Kiserud T. Fetal venous circulation - an update on hemodynamics. J Perinatol Med 2000;28:90-96.
- Skulstad SM, Kiserud T, Rasmussen S. The effect of vascular constriction on umbilical venous pulsation. Ultrasound Obstet Gynecol 2004;23:136-130.
- Hofstaetter C, Dubiel M, Gudmundsson S. Two types of umbilical venous pulsations and outcome of high-risk pregnancy. Early Hum Development 2001;61:111-117.
- Mari G, Hanif F, Drennan K, Kruger M. Staging of intrauterine growth-restricted fetuses. J Ultrasound Med 2007;26:1469-1477.
- Baschat AA, Gembruch U. Triphasic umbilical venous blood flow with prolonged survival in severe intrauterine growth retardation: a case report. Ultrasound Obstet Gynecol 1996;8:201-205.
- Turan OM, Turan S, Gengor S, Berg C, Moyano D, Gembruch U, Nicolaides KH, Harman CR, Baschat AA. Progression of Doppler abnormalities in intrauterine growth restriction. Ultrasound Obstet Gynecol 2008;32:160-167.
- Baschat AA, Galan HL, Bhide A, Berg C, Kush ML, Oepkes D, Thilaganathan B, Gembruch U, Harman CR. Doppler and biophysical assessment in growth restricted fetuses: distribution of test results. Ultrasound Obstet Gynecol 2006;27:41-7.
- American College of Obstetricians and Gynecologists (ACOG): Intrauterine growth restriction. ACOG Pract Bull 2000;12:1-12.
- Kaponis A, Harada T, MaKrydimas G, Kiyama T, Arata K, Adonakis G, Tsaponas V, Iwabe T, Stefos T, Decavalas G, Haraden T. The importance of venous Doppler velocimetry for evaluation of intrauterine growth restriction. J Ultrasound Med 2011;30;529-545.
- Miller J, Turan S, Baschat AA. Fetal Growth Restriction. Sem Perinatol 2008;32:274-280.