Doppler in Obstetrics by Nicolaides, Rizzo, Hecker & Ximenes
The 11-14 weeks scan by Nicolaides, Sebire, Snijiders & Ximenes
The 18-23 weeks scan by Pilu, Nicolaides, Ximenes & Jeanty
 
PATHOPHYSIOLOGY

Maternal diabetes mellitus is associated with a high risk of fetal death. In the past, before the introduction of insulin, the main cause of death was in association with maternal keto-acidosis, but now most fetal deaths are non-keto-acidotic and occur in association with fetal macrosomia.

The major source of fetal glucose is the mother and there is a good correlation between maternal and fetal blood glucose concentrations 1. In pregnancies complicated by diabetes mellitus, the maternal hyperglycemia causes fetal hyperglycemia and hyperinsulinemia 2,3. Furthermore, the fetal insulin to glucose ratio is increased because hyperglycemia and/or the other metabolic derangements associated with maternal diabetes mellitus act on the fetal pancreas to cause b -cell hyperplasia and precocious pancreatic maturation 2. Fetal hyperinsulinemia causes macrosomia, either directly through its anabolic effect on nutrient uptake and utilization, or indirectly through related peptides such as insulin-like growth factors 4.

Although good diabetic control in the third trimester of pregnancy reduces the incidence of macrosomia, the latter is not always preventable. In pregnant women with diabetes mellitus, despite stringent maternal glycemic control, the fluctuation in maternal glucose concentration is greater than in non-diabetics and it is possible that, during short-lived episodes of hyperglycemia, an already hyperplastic fetal pancreas will respond with a disproportionately high release of insulin.

In diabetic pregnancies, analysis of blood samples obtained by cordocentesis has demonstrated significant acidemia and hyperlacticemia in the absence of hypoxemia 5-7. Fetal acidemia, which may offer an explanation for the unexplained stillbirths of diabetic pregnancies, is likely to be the consequence of increased metabolic rate. Salvesen et al. performed cordocentesis in diabetic pregnancies and reported a significant association between fetal plasma insulin concentration and the degree of fetal acidemia 2. In pregnant sheep, chronic hyperglycemia results in increased aerobic and anaerobic glucose metabolism, with consequent increased oxygen consumption, lactate production and fall in pH and pO 28-13 . Glucose oxidation and oxygen consumption are also increased by hyperinsulinemia, and this effect is independent of that caused by hyperglycemia 12. Hyperlacticemia occurs because the fetus has a reduced capacity for oxidative metabolism and low pyruvate dehydrogenase activity. Severe hyperglycemia is characterized by acidemia and hypoxemia, but minor degrees of hyperglycemia are associated with acidemia in the absence of hypoxemia 8 . However, in the presence of mild fetal hypoxemia, minor degrees of fetal hyperglycemia do result in severe acidosis and even fetal death 13.

The alternative explanation for fetal acidemia in maternal diabetes mellitus is impaired placental perfusion. Histological studies have reported decreased villous surface area, villous edema and thickening of the basement membrane 14 . However, the finding that acidemia is not accompanied by hypoxemia suggests that the acidemia is unlikely to be due to impaired placental function; in pregnancies complicated by intrauterine growth restriction due to uteroplacental insufficiency, acidemia is accompanied by hypoxemia (see Chapter 4 ).

 
DOPPLER STUDIES OF THE UMBILICAL AND UTERINE ARTERIES

The aim of Doppler ultrasound studies of the umbilical and uterine arteries in diabetic pregnancies is to determine whether impedance to flow is related to maternal glycemic control and whether impedance is increased in patients with diabetic nephropathy and vasculopathy. This section also examines whether impedance in the uterine and umbilical arteries can provide useful prediction of subsequent development of preeclampsia and/or intrauterine growth restriction in the same way that it does in nondiabetic pregnancies.

Olofsson et al. examined 40 diabetic pregnancies and reported that the volume blood flow in the fetal aorta and umbilical vein and the pulsatility index (PI) in theumbilical artery were higher in diabetic than in non-diabetic pregnancies 15. There was no significant association between these indices and the degree of diabetic control or fetal size, but the high umbilical artery PI and high aortic volume flow occurred in fetuses who later developed distress in labor. It was suggested that, in some diabetic pregnancies, there is increased placental vascular resistance with a compensatory increase in volume flow. A high umbilical artery PI cannot be considered characteristic of diabetic pregnancy, but fetal distress might be more common in diabetic pregnancy 15 . More recently, Ursem et al. examined 16 women with well-controlled insulin-dependent diabetes mellitus at 12–21 weeks of gestation and reported increased fetal heart rate variability and umbilical artery peak systolic velocity, but normal fetal heart rate and umbilical artery time-averaged velocity 16. It was suggested that fetal heart rate variability and umbilical artery peak systolic velocity may be markers for fetal cardiovascular homeostasis in pregnancies complicated by insulin-dependent diabetes mellitus 16.

Bracero et al. performed Doppler studies of the umbilical artery during the third trimester of pregnancy in 43 women with diabetes mellitus 17. They found a significant association between impedance to flow and maternal serum glucose concentration. Furthermore, high impedance was associated with an increased number of stillbirths and neonatal morbidity. It was suggested that maternal hyperglycemia causes placental vasoconstriction by impairing prostacyclin production 17. In another study, Bracero et al. evaluated 207 singleton pregnancies complicated by maternal diabetes mellitus within 1 week of delivery. In 36% of cases, there was an adverse outcome (defined as delivery before 37 weeks, or fetal risk requiring Cesarean delivery, or fetal growth restriction, or neonatal hypocalcemia, hypoglycemia, hyperbilirubinemia, or respiratory distress syndrome) 18. The relative risk of adverse outcome was 2.6 for increased impedance in the umbilical artery, which was higher than the risk of 1.7 for abnormal biophysical profile score or a non-reactive non-stress test 18. Bracero et al. also measured impedance to flow in the left and right uterine arteries in 265 women with singleton pregnancies complicated by diabetes mellitus within 1 week before delivery 19 . The higher the difference in impedance between the two uterine arteries, the greater was the risk of adverse pregnancy outcome, but there was a considerable overlap in discordance between the good and adverse outcome groups.

Landon et a. performed serial measurements of impedance to flow in the umbilical artery in 35 insulin-dependent diabetic women, during the second and third trimesters, and found no significant association between this index and maternal blood glucose or glycosylated hemoglobin level 20.Women with vascular disease had a higher impedance in the umbilical artery compared to those with uncomplicated diabetes. Increased impedance in women with vascular disease was associated with subsequent development of intrauterine growth restriction and, in those with no vascular disease, with the development of pre-eclampsia. Similarly, Dicker et a. carried out Doppler examinations of the umbilical artery in 108 pregnant women with insulin-dependent diabetes mellitus and found no significant association between impedance to flow and maternal blood glucose or glycosylated hemoglobin levels 21. Increased umbilical artery impedance was associated with the subsequent development of pre-eclampsia (in women without vasculopathy) and development of intrauterine growth restriction in those with vasculopathy.

Reece et al. examined 56 diabetic pregnancies and reported that the umbilical artery PI was higher in patients with diabetic vasculopathy than in non-diabetic controls or in diabetic patients without vasculopathy. Intrauterine growth restriction and neonatal metabolic complications were also significantly correlated with elevated umbilical artery PI 22. There was, however, no correlation between Doppler indices and maternal glucose values, although most were within a euglycemic range.

Ishimatsu et al. performed Doppler studies of the umbilical artery during the third trimester of pregnancy in 16 women with diabetes mellitus. They found no significant association between impedance to flow and maternal serum glucose or fructosamine levels 23. However, in two patients with serum glucose levels of over 300 mg/dl, impedance was increased and returned to the normal range when the serum glucose level decreased to below 200 mg/dl.

Johnstone et al. measured impedance to flow in the umbilical artery in 128 pregnancies complicated by diabetes mellitus 24. There was no significant association between impedance to flow and either short-term or long-term glycemic control. Although, in some cases that subsequently developed fetal distress, there was increased impedance, fetal compromise also occurred in association with normal impedance.

Zimmermann et al. carried out serial measurements of impedance to flow in the umbilical artery in 53 women with insulin-dependent diabetes. Impedance was within the normal range and there was no significant association with maternal blood glucose or glycosylated hemoglobin level or maternal vascular disease 25. This group also measured impedance to flow in the uterine arteries in 43 pregnancies complicated by insulin-dependent diabetes mellitus and found no significant differences from normalor significant associations with short- and long-term glycemic control, maternal vasculopathy, or diabetes-specific fetal morbidity 26.

The effectiveness of screening for the complications of impaired placentation by uterine artery Doppler in diabetic pregnancies may be similar to that in non-diabetics 27. Thus, Haddad et al. measured impedance to flow in the uterine arteries of 37 diabetic pregnancies and reported that increased impedance identified 45% of those that subsequently developed pre-eclampsia and/or intrauterine growth restriction. Barth et al. measured impedance to flow in the uterine arcuate artery system beneath the placenta within 8 days of delivery in 47 patients with insulin-dependent diabetes mellitus and reported increased impedance in those cases where histological examination of the decidual arteries after delivery showed severe vasculopathy 28. The study confirmed a relationship between arcuate artery Doppler indices and downstream decidual vascular pathology. Kofinas et al. examined 31 pregnant women with gestational diabetes and 34 with insulin-dependent diabetes mellitus. Impedance to flow in the umbilical and uterine arteries during the third trimester was not different between patients with good glycemic control and those with poor control 29. In contrast, impedance was significantly higher in patients with pre-eclampsia than in those without pre-eclampsia, regardless of glycemic control. It was concluded that Doppler investigation may be clinically useful only in diabetic pregnancies complicated by pre-eclampsia.

 
DOPPLER STUDIES OF THE FETAL MIDDLE CEREBRAL ARTERY AND AORTA

Diabetes mellitus is associated with an increased risk of fetal death, and data from cordocentesis have demonstrated an association between maternal hyperglycemia and fetal acidemia. The aim of Doppler ultrasound studies of the fetal middle cerebral artery and aorta is to examine whether the compromised fetus of a diabetic pregnancy demonstrates the same features of circulatory redistribution as seen in fetal hypoxemia due to uteroplacental insufficiency.

Salvesen et a. carried out a longitudinal Doppler study in 48 relatively wellcontrolled diabetic pregnancies 30. With the exception of three pregnancies complicated by pre-eclampsia and/or intrauterine growth restriction, the uteroplacental and fetoplacental circulations were essentially normal. Thus, impedance to flow in the uterine and umbilical arteries and the PI or mean velocity in the middle cerebral artery or descending thoracic aorta were not significantly different from normal. It is of particular interest that normal Doppler results in the uterine and umbilical arteries and the fetal middle cerebral artery and aorta were also observed in five of six patients with diabetic nephropathy 31. In all cases, iatrogenic delivery was carried out at 27–36 weeks because of worsening maternal proteinuric hypertension. Cordocentesis, performed within 24 hours before delivery, demonstrated these fetuses to be hypoxemic and acidemic. It was concluded that fetal acidemia in pregnancies complicated by diabetic nephropathy is not a consequence of impaired placental perfusion, and the degree of metabolic derangement may be obscured by the apparent normal growth of these fetuses and their failure to demonstrate blood flow redistribution. Another conclusion from this study is that uterine artery Doppler may be useful in distinguishing true pre-eclampsia (increased PI) from renal proteinuria and hypertension (normal PI).

Ishimatsu et al. measured impedance to flow in the fetal middle cerebral artery in 43 pregnant women with well-controlled diabetes mellitus at 24–38 weeks of gestation 32. The PI was within the normal range and was not significantly associated with maternal serum glucose, fructosamine or glycosylated hemoglobin level. Reece et al. Examined 30 pregnant women with insulin-dependent diabetes mellitus at 2-week intervals between 18 and 38 weeks of gestation 33. They found no significant association between impedance to flow in the fetal aorta and fetal outcome. They concluded that fetal aortic Doppler velocimetry cannot be used as a means of assessing impending fetal compromise in offspring of diabetic mothers.

 
DOPPLER STUDIES OF THE FETAL HEART

Infants of diabetic mothers are at increased risk of hypertrophic cardiomyopathy. This disease is characterized by a thickening of the interventricular septum and ventricular walls and by systolic and diastolic dysfunction, which may result in congestive heart failure.

Rizzo et al. examined 40 well-controlled insulin-dependent diabetic pregnancies at 20–38 weeks of gestation and reported a significant increase in fetal interventricular septal thickness (Figure 1) and an associated decrease in the ratio between the peak velocities during early passive ventricular filling and active atrial filling at the level of the atrioventricular valves 34. These findings, which were unrelated to maternal glycosylated hemoglobin levels, suggest that, even in well-controlled maternal diabetes mellitus, there is fetal interventricular septal hypertrophy that affects cardiac diastolic function. A longitudinal study of 14 well-controlled, insulin-dependent diabetic pregnancies at 20–36 weeks of gestation confirmed the presence of hypertrophy in the interventricular septum and the right and left ventricular walls, as well as abnormal development of cardiac function – decrease in the ratio between early and active ventricular filling at the level of both the mitral and tricuspid valves (Figure 2) 35. The cardiomegaly and cardiac dysfuncion increased with gestation but they were evident from as early as 20 weeks. Since the diabetic control in these pregnancies was good, it was suggested that fetal cardiomegaly may be the consequence of increased insulin sensitivity of the fetal myocardium. This hypothesis is supported by the data of Thorsson and Hintz, showing a reduction from fetus to adult in the number and affinity of insulin receptors 36.

Figure 1: Real-time and M-mode tracing of a fetus of an insulindependent diabetic mother at 36 weeks of gestation. The interventricular wall septal thickness is increased (10 mm compared to the expected mean of 5 mm for this gestation)
Figure 2: Flow velocity waveforms across the tricuspid valve in a fetus of an insulin-dependent diabetic mother at 32 weeks of gestation. The E/A ratio is decreased (0.48 compared to expected mean of 0.77 for this gestation)

The lower ratio between early and active ventricular filling at the level of the atrioventricular valves in fetuses of diabetic mothers may be due to impaired development of ventricular compliance, possibly secondary to cardiac wall thickening. In addition, the ratio may be influenced by reduced preload, as a consequence of the polycythemia, and therefore increased blood viscosity in fetuses of diabetic mothers. Thus, in a Doppler study of 37 fetuses of insulin-dependent diabetic mothers, immediately before an elective Cesarean section, the ratio between early and active ventricular filling was significantly and independently affected by both the interventricular wall thickness and fetal hematocrit 37.

Weber et al. performed serial evaluations of cardiac growth and ventricular diastolic filling using M-mode and Doppler echocardiography at 20–40 weeks of gestation and at 48–72 hours after birth in 11 fetuses of non-diabetic mothers and nine fetuses of well-controlled insulin-dependent diabetic mothers. Cardiac growth and birth weight in the two groups were similar 38. Ventricular diastolic filling increased with gestation in both groups but the increase was delayed in the diabetic group. Tsyvian et al. examined 15 third-trimester pregnancies complicated by insulin-dependent maternal diabetes mellitus and reported a delay in fetal left ventricular filling, which may reflect changes in myocardial relaxation 39. Weiner et al. examined 31 well-controlled insulin-dependent diabetic pregnancies at 22–40 weeks of gestation and reported that, after 34 weeks, in the fetuses of diabetic pregnancies, compared to normal pregnancies, there was a lower ratio between the peak velocities during early passive ventricular filling and active atrial filling at the level of the atrioventricular valves 40.

Macklon et al. examined well-controlled diabetic pregnancies at 18–20 weeks of gestation and reported that the fetal intraventricular septal thickness was increased, but transvalvular peak flow velocities and the duration of ventricular ejection in the fetal heart were not significantly different from normal 41. It was concluded that, in fetuses of well-controlled diabetic pregnancies, altered cardiac morphology is evident early in pregnancy, before any obvious alteration in cardiac function. Rizzo et al. examined 27 insulin-dependent diabetic pregnancies from 12 weeks of gestation 42. In the fetuses of diabetic mothers, compared to normal pregnancies, there was a lower ratio between early and active ventricular filling at the level of the atrioventricular valves, a higher percentage of reverse flow during atrial contraction in the inferior vena cava, and a higher proportion of cases with pulsations in the umbilical vein. These findings, demonstrating impaired development of cardiac and venous blood flow patterns from as early as at 12 weeks of gestation, were more evident in pregnancies with poorer glycemic control but they were also found in the presence of good metabolic control.

Peak velocities at the level of the aortic and pulmonary outflow tracts were significantly higher in fetuses of diabetic mothers than in normal fetuses 34. The most likely explanations for the increased peak velocities are increased cardiac contractility (also found in postnatal studies in infants of diabetic mothers) and increased intracardiac flow volume due to the relatively large size of such fetuses, since cardiac output is a function of fetal weight. These abnormalities in cardiac hemodynamics also impair the venous circulation. Rizzo et al. carried out a cross-sectional study of 62 third-trimester fetuses in insulin-dependent diabetic pregnancies and reported that increased preload index in the inferior vena cava (in the absence of alterations in fetal peripheral vessels) was associated with a lower umbilical arterial blood pH and higher hematocrit at birth, as well as increased neonatal morbidity 43. These findings suggest that the mechanisms inducing fetal distress in diabetic pregnancies (where the development of hypertrophic cardiomyopathy plays a pivotal role in the genesis of fetal distress) are different from those in fetuses with intrauterine growth restriction, where the change in cardiac function is secondary to the alteration in peripheral resistance.

In neonates from normal pregnancies, the ratio between early and active ventricular filling at the level of the atrioventricular valves increases during the first few days of postnatal life; the early wave is usually higher than the active one, resulting in a ratio between early and active ventricular filling that is higher than one. In newborns of diabetic mothers, there are no changes in this ratio during the first 5 days of life and its value remains lower than one 44. These anomalies might explain the relatively high incidence of transitory tachypnea and pulmonary edema in neonates from diabetic pregnancies. The cardiac hypertrophy of fetuses of diabetic mothers resolves during the first year of postnatal life. However, it is possible that the cardiac hypertrophy and dysfunction observed in intrauterine life may affect cardiac function in adult life.

 
CONCLUSIONS
  • In maternal diabetes mellitus, impedance to flow in the uterine and umbilical arteries is not related to either short-term or long-term maternal glycemic control.
  • In maternal diabetes mellitus, impedance to flow in the uterine arteries is normal, even in patients with nephropathy and vasculopathy. However, increased impedance, as in non-diabetic pregnancies, identifies a group at high risk for subsequent development of pre-eclampsia and/or intrauterine growth restriction.
  • In maternal diabetes mellitus, increased impedance to flow in the umbilical artery is associated with the development of pre-eclampsia and/or intrauterine growth restriction. There is contradictory evidence concerning a possible increase in impedance in pregnancies with maternal vasculopathy.
  • In maternal diabetes mellitus, there is no evidence of redistribution in the fetal circulation with decreased PI in the middle cerebral artery and increased PI in the descending thoracic aorta. This is presumably because, in diabetes, there may be acute fluctuations in fetal blood pH, since the latter is associated with the maternal glucose concentration. Furthermore, unlike intrauterine growth restriction, in diabetes metabolic derangements in the fetus may lead to acidemia without hypoxemia. Therefore, the classic redistribution seen in fetal hypoxemia due to uteroplacental insufficiency may not occur even in severely compromised fetuses, and it is therefore important not to be misled by apparently normal fetal Doppler results.
  • In maternal diabetes mellitus, the fetus is at increased risk of hypertrophic cardiomyopathy. This disease is characterized by a thickening of the interventricular septum and cardiac dysfunction, which may be evident from as early as 12 weeks of gestation.
 
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Doppler in Obstetrics
Copyright © 2002 by Kypros Nicolaides, Giuseppe Rizzo, Kurt Hecker and Renato Ximenes
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