Original Article
Diagnostic Value of Blood Sampling in Fetuses with Growth Retardation
N Engl J Med 1993; 328:692-696March 11, 1993
- Abstract
Background
Fetuses with intrauterine growth retardation are delivered if they have evidence of distress, as manifested by abnormalities in the fetal heart rate and umbilical-artery blood flow. We studied whether umbilical-blood sampling might provide further information useful for management.
Methods
We measured hemoglobin and lactate concentrations, oxygen content, pH, blood gas levels, and base deficit in umbilical-vein blood and correlated these measurements with the heart rate and umbilical-artery wave forms recorded by Doppler velocimetry in 56 fetuses with growth retardation. Twenty-one fetuses had normal heart rates and normal results of velocimetry, 24 had normal heart rates and abnormal results of velocimetry (indicative of decreased diastolic flow), and 11 had abnormal heart rates and abnormal results of velocimetry.
Results
None of the 21 fetuses with normal heart rates and velocimetry had hypoxia or acidemia. Of the 24 fetuses with normal heart rates and abnormal velocimetry, 4 (17 percent) had moderate lactic acidosis, 1 (4 percent) had a low pH value, and 3 (12 percent) had hypoxia. Of the 11 fetuses with abnormal heart rates and velocimetry, 7 (64 percent) had lactic acidosis, low blood oxygen content, and low pH values. The absence of end-diastolic flow increased the risk of hypoxia and acidemia. The proportion of fetuses with elevated hemoglobin concentrations was similar among the three groups.
Conclusions
Assessment of fetal oxygenation and acid-base balance is not indicated in fetuses with growth retardation if their heart rates and the results of velocimetry are normal. If the results of velocimetry are abnormal, fetal-blood sampling can distinguish fetuses that have growth retardation alone from those that also have hypoxia and acidosis, and thus may aid in determining the optimal time of delivery.
Media in This Article
Figure 1
Lactate Concentration and Oxygen Content in Umbilical Venous Blood in Three Groups of Fetuses with Growth Retardation.Figure 2
Umbilical Venous PO2 Values as a Function of Gestational Age.Article Activity
- Article
Intrauterine growth retardation is an important cause of perinatal mortality and morbidity,1,2 and infants with this disorder have a greater risk of handicaps in later childhood2. At present, no intrauterine therapy is available for affected fetuses: delivery is the best treatment. The timing of delivery is based on an evaluation of the fetal heart rate, amniotic-fluid volume, and fetal movements, as well as on the level of fetal maturity.
A number of studies have also suggested a clinical role for measurements of fetal-blood-flow wave forms, particularly in the umbilical artery, by Doppler velocimetry3,4. All these techniques are relatively noninvasive and can be performed repeatedly without risk to the fetus. More recently, the availability of techniques for sampling cord blood in utero has offered the opportunity to assess the metabolic environment of the fetus before parturition. Fetal-blood samples obtained by cordocentesis have been used to detect the presence of hypoxia,5 acidemia and lactic acidosis,5,6 low amino acid concentrations,7 and endocrine abnormalities8 in fetuses with growth retardation. In theory, fetal-blood sampling could enhance the predictive value of measurements of the fetal heart rate9 and Doppler velocimetry10,11 and provide further information about these fetuses, documenting the metabolic abnormalities most frequently found at different gestational ages in relation to the type and severity of growth retardation. However, fetal-blood sampling is an invasive technique with definable risks to the fetus that range from minor complications such as bleeding and bradycardia (6.6 percent) to premature rupture of the membranes (0.4 percent) and death (0.8 percent)12.
The goal of our study was to compare two biophysical, noninvasive measurements (recording of the fetal heart rate and Doppler velocimetry of the umbilical artery) with biochemical measurements obtained by fetal-blood sampling (the hemoglobin concentration, oxygen content, pH, blood gas levels, base deficit, lactate concentration, and plasma concentrations of branched-chain amino acids in umbilical venous blood) in a group of fetuses with severe growth retardation, to help clarify the role of these procedures in the management of pregnancies involving such fetuses.
Methods
The studies were performed in the Department of Obstetrics and Gynecology of the San Paolo Institute of Biomedical Sciences. The protocol was approved by the San Paolo Institute Board and the Human Subjects Committee of the University of Colorado School of Medicine. Informed consent was obtained from all the pregnant women.
Subjects
The study series includes 58 consecutive fetuses with intrauterine growth retardation diagnosed by ultrasonography between 26 and 37 weeks of gestation. Gestational age was determined according to the onset of the last menstrual period and by an ultrasonographic examination performed before 20 weeks of gestation. Ultrasonographic measurements of the head and abdominal circumferences of these fetuses were below the fifth percentile of reference values for fetuses of similar ages. All 58 fetuses had normal karyotypes and no malformations at birth. Growth retardation was confirmed at birth if the neonatal weight was below the 10th percentile according to Italian standards for birth weights and gestational age13. The birth weights of 42 of the 58 (72 percent) were below the fifth percentile.
The measurements of the hemoglobin concentration, oxygen content, pH, blood gas levels, base deficit, lactate concentration, and plasma concentrations of branched-chain amino acids in umbilical venous blood from the 58 fetuses were compared with those in 61 normal fetuses that underwent cordocentesis between 17 and 39 weeks of gestation for prenatal diagnosis (14 for rapid karyotyping, 13 for hematologic disorders such as β-thalassemia, Rh factor disease, or thrombocytopenia, 24 for congenital infections, and 10 for other indications). These 61 fetuses were subsequently found not to be affected by the condition under investigation.
Fetal Blood Sampling
Fetal blood was obtained from the umbilical vein as previously described14. The site of sampling was assessed by ultrasonographic imaging with a 5-MHz sector transducer, by determination of the nonpulsatile flow in the vessel, and by imaging the direction of flow by observing the bubbling effect produced by the injection of 2 ml of isotonic saline solution.
Biochemical Analyses
Blood for all analyses was collected into heparin-treated syringes, which were immediately sealed and stored on ice; the determinations of lactate concentrations and levels of respiratory gases were carried out within 5 to 10 minutes after sampling. Care was taken to handle all blood samples as anaerobically as possible. The hemoglobin concentration and oxygen saturation were determined with an oximeter (Radiometer OSM-2). Oxygen content was calculated from these values according to the following equation: oxygen content (in millimoles per liter) = hemoglobin (in grams per liter) × oxygen saturation × 0.05982.
The blood pH, partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), and base deficit were determined with a Radiometer ABL 330 analyzer. Blood lactate concentrations were measured in duplicate with a Yellow Springs 23L analyzer. Plasma amino acid concentrations were measured as previously described7; we report here the concentrations for the three branched-chain amino acids valine, leucine, and isoleucine, since they have been found to be responsible for the significantly lower umbilical venous plasma concentrations of total α-aminonitrogen in fetuses with intrauterine growth retardation, as compared with fetuses with normal growth7.
Velocimetry and Heart-Rate Measurement
The wave form of the fetal umbilical-artery blood flow was measured by Doppler velocimetry immediately before fetal-blood sampling. A coaxial pulsed Doppler velocimeter with a sample volume of 5 mm and high-pass filters set at 100 Hz were used (Ultramark 5, ATL Corp.), with the lowest possible settings for energy output. For each reading, three consecutive wave forms were measured on hard copies by means of a computerized planimeter. The pulsatility index was measured according to the simplified Gosling formula (systolic velocity minus diastolic velocity divided by mean velocity)15; the mean velocity was calculated by dividing the area of the maximal velocity by the length of the cycle. The reference values were those obtained in our laboratory from a cross-sectional study of 440 normal fetuses16. The decrease in the diastolic velocity, which is quantified by the pulsatility index, is generally accepted as an indication of placental impedance to blood flow; the absence of end-diastolic flow correlates with the presence of severe placental damage.
The fetal heart rate was recorded immediately before blood sampling. The tracings were examined independently by two investigators who did not know the fetal-blood biochemical values or the results of Doppler velocimetry when they examined the tracings.
The criteria commonly used to evaluate a tracing of the fetal heart rate are the degree of variability and the presence of accelerations from the base line and the presence of decelerations in heart rate after Braxton Hicks contractions. A tracing was considered abnormal if at least one of the following patterns was present: less than two accelerations of the heart rate to an amplitude of ≥ 10 beats per minute lasting ≥ 15 seconds during a period of at least 30 minutes; variability of ≤ 5 beats per minute during a period of at least 60 minutes; and U-shaped (late) decelerations in the heart rate after Braxton Hicks contractions. The tracings of 11 fetuses were considered abnormal on the basis of one or more of the above criteria. Because the two examiners disagreed about the classification of the tracings of 2 of the 58 fetuses, those 2 were excluded from further analysis.
Statistical Analysis
The measurements in the fetuses with growth retardation were analyzed by calculating Pearson product-moment correlation coefficients. Two-tailed unpaired Student's t-tests were used to detect any significant difference between the normal fetuses and groups of the affected fetuses in the sum of the plasma concentrations of branched-chain amino acids.
Results
The fetuses with growth retardation were divided into three groups according to their fetal heart rates and the pulsatility indexes of the umbilical artery: group 1 consisted of 21 fetuses with normal heart rates and normal pulsatility indexes; group 2, 24 fetuses with normal heart rates and pulsatility indexes more than 2 SD above the mean in the normal fetuses; and group 3, 11 fetuses with abnormal heart rates and pulsatility indexes more than 2 SD above the normal mean. A fourth possible group (fetuses with abnormal heart rates and normal pulsatility indexes) was excluded since in this series an abnormal fetal heart rate was invariably associated with an abnormal pulsatility index.
The mean gestational age of each study group at the time of the studies and the mean values for variables that are independent of gestational age (blood oxygen content, pH, lactate concentration, and base deficit) are shown in Table 1Table 1
Gestational Age, Blood Oxygen Content, Blood Lactate Concentrations, and pH and Base-Deficit Values in 61 Normal Fetuses and 56 Fetuses with Growth Retardation., and lactate concentrations in umbilical venous blood plotted against blood oxygen content are shown in Figure 1Figure 1Lactate Concentration and Oxygen Content in Umbilical Venous Blood in Three Groups of Fetuses with Growth Retardation..All the fetuses in group 1 had normal oxygenation and blood lactate concentrations. In group 2, one fetus had a low pH (7.28), three fetuses had oxygen-content values below 4.2 mmol per liter, and four had moderately high blood lactate (1.6, 1.6, 2.0, and 2.2 mmol per liter, respectively). In group 3, 7 of the 11 fetuses (64 percent) had blood lactate concentrations above 1.5 mmol per liter, oxygen-content values below 4.2 mmol per liter, and pH values below 7.30. However, even in this group with abnormal fetal heart rates and abnormal pulsatility indexes, four fetuses had normal values for blood oxygen content and lactate concentration.
The umbilical venous PO2 and PCO2 and the hemoglobin concentrations in the three groups were plotted as a function of gestational age (Figure 2Figure 2
Umbilical Venous PO2 Values as a Function of Gestational Age., Figure 3Figure 3
Umbilical Venous PCO2 Values as a Function of Gestational Age., and Figure 4Figure 4
Hemoglobin Concentrations in Umbilical Venous Blood, as a Function of Gestational Age., respectively). As compared with normal fetuses, 7 of the 11 fetuses in group 3 had low PO2 values. PCO2 was increased in 11 fetuses (2 in group 1, 3 in group 2, and 6 in group 3). Similarly, hemoglobin concentrations were increased in 16 fetuses (4 in group 1, 9 in group 2, and 3 in group 3). There was a significant inverse correlation between the hemoglobin concentration and PO2 in umbilical venous blood in all three groups (r = -0.28, P = 0.04).End-diastolic flow was found to be absent or reversed in 16 fetuses in groups 2 and 3. The proportion in group 2 who had normal pH values was significantly higher than that in group 3 (100 percent [7 of 7 fetuses] vs. 44 percent [4 of 9], P = 0.02). There was no significant difference between group 2 and group 3 in the proportion of fetuses with high blood lactate concentrations (43 percent [3 of 7 fetuses] vs. 78 percent [7 of 9], P = 0.15). Fetuses with absence or reversal of end-diastolic flow and abnormal heart rates were significantly more likely to have hypoxia than fetuses with absence or reversal of end-diastolic flow alone (67 percent [6 of 9 fetuses] vs. 14 percent [1 of 7], P = 0.007).
Plasma concentrations of valine, leucine, and isoleucine were measured in 10 fetuses in group 1, 6 in group 2, and 3 in group 3. The mean (±SD) concentrations were 388 ±75 μmol per liter in group 1, 414 ±51 μmol per liter in group 2, and 355 ±35 μmol per liter in group 3; all these values were significantly lower than the mean for the normal fetuses (471 ±48 μmol per liter; P = 0.001, P = 0.05, and P = 0.01, respectively).
Discussion
Fetal growth retardation is not necessarily associated with abnormalities of the fetal heart rate and fetal vessels on Doppler velocimetry. In this selected series of 56 fetuses with intrauterine growth retardation that had normal karyotypes and no major malformations, 21 had both normal heart-rate patterns and normal umbilical-artery pulsatility indexes. No fetus had hypoxia or acidemia. Thus, fetal-blood sampling does not appear to be indicated for assessing oxygenation and acid-base balance in such fetuses.
When the umbilical-artery pulsatility index is abnormal but the fetal heart rate is normal, as in group 2, fetal hypoxia and acidosis are uncommon. We found a moderate degree of lactic acidemia in 4 of the 24 fetuses in this group, including 3 of the 7 fetuses in which end-diastolic flow was absent or reversed. Blood sampling may be indicated in the latter fetuses since elevated lactate concentrations may precede severe hypoxia and acidosis6,17 and hence mandate delivery, particularly when the gestational age is relatively advanced (>32 weeks) and neonatal survival rates exceed 90 percent.
Although the risk of hypoxia and acidosis was very high in group 3, not all the fetuses in this group had hypoxia and acidosis. Since neonatal mortality and morbidity are high among very premature infants with growth retardation,1,2 every effort should be made to delay delivery until the gestational age is at least 30 to 32 weeks. Blood sampling can help by identifying the fetuses (approximately 40 percent) that do not have hypoxia and acidemia despite having abnormal fetal heart rates and umbilical-artery pulsatility indexes.
An obvious limitation of fetal-blood sampling is that it provides values for only one point in time, and the values could change relatively quickly. Moreover, the samples are obtained from the umbilical vein; values measured in umbilical arterial blood may be better indicators of fetal hypoxia or acidemia, but sampling of the artery carries an increased risk of bleeding and bradycardia12.
Abnormal heart-rate patterns have previously been observed in fetuses with intrauterine growth retardation that had hypoxemia, acidemia, or both, whereas normal heart-rate patterns have generally been found in fetuses with growth retardation whose PO2 values were in the lower normal range9,18. However, in 6 of 45 fetuses with growth retardation, PO2 values were below the normal range even when the fetal heart rate was normal9. We found that fetuses with normal heart rates had normal PO2 levels and higher hemoglobin concentrations and that their PO2 values correlated with their hemoglobin values; these findings may reflect chronic, relatively mild hypoxia or intermittent episodes of more severe hypoxia not detected by examination of umbilical venous blood.
In previous studies of Doppler velocimetry and umbilical-blood gas measurements in fetuses with growth retardation,10,11 an increase in umbilical-artery flow ratios (the systolic:diastolic ratio or the pulsatility index) was found to be related to the degree of hypoxia and lactic acidemia, especially when end-diastolic flow was absent. Our results indicate that absence or reversal of end-diastolic flow is associated with hypoxia and acidosis, but the association is not invariable and it is strengthened when fetal-heart-rate patterns are abnormal.
The sequence of metabolic and circulatory events that leads to fetal growth retardation is not known. However, in our series, none of the fetuses with a normal pulsatility index had an abnormal heart rate. Thus, velocimetry is a useful, noninvasive screening procedure: it appears to offer adequate surveillance, without a need for fetal-heart-rate monitoring or fetal-blood sampling, if its results are normal. Since the umbilical-artery pulsatility index is considered to be an indicator of placental vascular resistance,19 these findings suggest that placental vascular changes usually precede any evidence of changes in the fetal heart rate, hypoxia, and acidosis. Other investigators have shown that changes in umbilical-artery wave forms usually precede abnormalities in the fetal heart rate20.
We detected decreased concentrations of branched-chain amino acids, which may reflect altered placental transport of amino acids,7 in all three groups of fetuses, suggesting that impairment of amino acid transport and metabolism occurs early in the course of intrauterine growth retardation and independently of hypoxia, presumably as a function of poor placental growth and maturation.
In conclusion, assessment of fetal oxygenation and acid-base balance is not indicated in fetuses with intrauterine growth retardation if the results of Doppler velocimetry of the umbilical artery and measurement of the heart rate are normal. If the results of velocimetry are abnormal, fetal-blood sampling can distinguish normal fetuses that have growth retardation alone from fetuses with this disorder that also have hypoxia and acidosis, and hence help in identifying the optimal timing of delivery according to the level of fetal maturity.
Supported by the Italian National Research Council (Targeted Project, Prevention and Control Disease Factors; Subproject, FATMA [91.00215.PF41.115.21807]), by a grant (0191/88) from the North Atlantic Treaty Organization, and by a grant (HD-20761) from the National Institutes of Health.
Source Information
From the Department of Obstetrics and Gynecology, San Paolo Institute of Biomedical Sciences, University of Milan, Italy (G.P., I.C., A.M.M., A.L., P.B., E.F., M.B.), and the Division of Perinatal Medicine, Department of Pediatrics, University of Colorado School of Medicine, Denver (F.C.B.).
Address reprint requests to Dr. Pardi at the Department of Obstetrics and Gynecology, University of Milan, H. San Paolo, Via A. di Rudini, 8, 20142 Milan, Italy.
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