Role of the Pulmonary Circulation in the Distribution of Human Fetal Cardiac Output During the Second Half of Pregnancy
Background By using Doppler echocardiography, we determined the normal distribution of human fetal combined cardiac output (CCO) from the left and right ventricles. We also established weight-indexed pulmonary and systemic vascular resistances (RPi and RSi, respectively) and changes during the second half of pregnancy.
Methods and Results Blood flows at the aortic and pulmonary valve annuli (LVCO and RVCO, respectively), right and left pulmonary arteries (QP), and ductus arteriosus (QDA) were calculated in 63 normal fetuses. Foramen ovale blood flow (QFO=LVCO−QP) was estimated. From 20 to 30 weeks of gestation, the proportion of QP of the CCO increased (from 13% to 25%, P<.001), while the proportion of QFO decreased (from 34% to 18%, P<.001). After 30 weeks, the proportions of QP and QFO were unchanged. At 38 weeks, the proportion of RVCO (60%) was higher (P<.05) than that of LVCO (40%). The proportion of QDA did not change significantly. The correlation between RVCO calculated from blood flow through the pulmonary valve and from QDA and QP was good (r=.97, P<.0001). RPi (P<.001) decreased from 20 to 30 weeks of gestation. From 30 to 38 weeks, RPi increased (P<.0001). RSi increased (P<.001) from 20 to 38 weeks. The ratio of RPi to RSi decreased (P<.01) from 20 to 30 weeks and later remained unchanged.
Conclusions The human fetal pulmonary circulation has an important role in the distribution of cardiac output.
The development of Doppler ultrasound techniques has made it possible to evaluate human fetal hemodynamics noninvasively. Previously published studies on the distribution of human fetal cardiac output have concentrated on the relationship between RVCO and LVCO during the second half of pregnancy.1 2 3 Fetal pulmonary blood flow and its proportion of total cardiac output has been estimated indirectly by measuring RVCO, LVCO, and volumetric blood flow through the ductus arteriosus.4
In this study, we asked two questions: What are the normal relative RVCO and LVCO in the human fetus, and what changes occur in the human fetal weight-indexed pulmonary and systemic vascular resistances during the second half of pregnancy?
Sixty-three normal singleton fetuses in uncomplicated pregnancies referred for fetal echocardiography were studied in a cross-sectional manner between 19 and 39 weeks of gestation (median, 28 weeks). The Research Review Committee of our institution approved the research protocol, and each patient gave written consent for Doppler studies. In all cases, the gestational age was confirmed by ultrasound study before 20 weeks of gestation. According to fetal biometry, each fetus was appropriate for gestational age in size (>10th percentile growth curve). In all cases, amniotic fluid volume was estimated to be normal, and fetal anatomic surveys did not reveal any abnormalities. Maternal age varied between 17 and 40 years, and gestational age at delivery was ≥36 weeks in each case. Mean birth weight was 3307 g (range, 2506 to 4266 g), and 1- and 5-minute Apgar scores were at least 6 and 8, respectively.
Image-directed pulsed and color Doppler equipment (Acuson 128 XP) was used with a 5-MHz sector probe to obtain the blood velocity waveforms at the level of AV, PV, DA, RPA, and LPA (immediately after the bifurcation of the main pulmonary artery). The lowest high-pass filter level was used (100 Hz), and the spatial-peak temporal average power output for color and pulsed Doppler was kept at <100 mW/cm2. An angle <15° between the vessel and Doppler beam was accepted for analysis. From Doppler tracings, FHR (in beats per minute) was measured, and the TVIs (in centimeters) were calculated by planimetering the area underneath the Doppler spectrum. At least three consecutive cardiac cycles were analyzed, and their mean value was used for further analysis. The diameters of the AV and PV annuli, DA, and both branch pulmonary arteries were measured from frozen real-time images during systole by using the leading edge–to–leading edge method. At least three separate measurements of vessel diameters were done, and the mean values were calculated. Calculation of the cross-sectional area (A; in centimeters squared) of the vessels was based on the assumption that the cross sections of the vessels were circular. All these measurements were performed by one examiner (Dr Rasanen).
Volumetric blood flow (Q; in milliliters per minute) in the artery was calculated with this formula: Q=FHR×A×TVI. LVCO equals the blood flow through the AV; RVCO equals the blood flow through the PV, respectively. CCO is the sum of LVCO and RVCO. Total pulmonary blood flow (QP) was calculated by combining right and left pulmonary artery blood flows. The volume blood flow through foramen ovale (QFO) was estimated by subtracting QP from LVCO. To evaluate the validity of our methodology, we correlated RVCO on the basis of two independent calculations: blood flow through the PV and RVCO based on the sum of QP and QDA.
Weight-indexed pulmonary and systemic vascular resistances (RPi and RSi, respectively) were calculated by using this formula: Ri=P/Qi, where P is blood pressure (in millimeters of mercury) and Qi is weight-indexed volume blood flow (in milliliters per minute per kilogram). Weight-indexed systemic volume blood flow (QSi) was calculated by subtracting weight-indexed pulmonary volume blood flow (QPi) from weight-indexed CCO. Fetal weight estimation was based on the measurements of fetal head and abdominal circumferences and femur length. This combination is the most accurate method (1 SD=7.5% of actual weight) for estimating fetal weight.5 The fetal mean transpulmonary pressure gradient was assumed to be equal to the mean systemic blood pressure. At 20 weeks of gestation, human fetal blood pressure is ≈30 to 35 mm Hg.6 At 30 and 38 weeks of gestation, fetal blood pressure values were assumed from values in newborns at the same gestational age.7 The weight-indexed vascular resistances and their relationships were analyzed at three different gestational ages: 20 (n=13), 30 (n=13), and 38 (n=14) weeks of gestation.
Linear or polynominal regression analysis was used to show the relationship of measured parameters to gestational age. Comparison between different gestational age groups was done with ANOVA. If statistical significance was reached between the gestational age groups, Fisher's test was used for further analysis. The comparison between different parameters in the same patient was performed by using paired Student's t test. A value of P<.05 was used as the level of statistical significance.
The area and TVI of AV and PV annuli, DA, RPA, and LPA increased significantly with advancing gestational age (Table 1⇓ and Fig 1⇓), as did RVSV and LVSV (Fig 2⇓). The RVSV-to-LVSV ratio was greater (P<.01) at term of pregnancy (>36 weeks of gestation) (1.54±0.27, mean±SD) than at 19 to 22 weeks of gestation (1.17±0.25; Fig 2⇓). Fetal CCO, RVCO, and LVCO increased >10-fold from 20 weeks to term, and QDA, QFO, and QP also increased significantly with advancing gestation (Fig 3⇓). PV area, RVSV, and RVCO were greater (P<.0001) than AV area, LVSV, and LVCO. The ratio between PV and DA area increased significantly from 20 weeks of gestation to term (Table 1⇓). The DA area was greater (P<.0001) than LPA or RPA area, but the ratio between LPA or RPA and DA area increased significantly with advancing gestation (Table 1⇓). No statistically significant differences in the area, TVI, or volume blood flow between right and left pulmonary arteries existed. The correlation between RVCO calculated from PV and RVCO calculated from QDA+QP was good (r=.97, P<.0001; Fig 4⇓).
A significant correlation existed between gestational age and RVCO, LVCO, QFO, and QP proportion of the CCO (Fig 5⇓). From 20 to 30 weeks of gestation, the proportion of QP (P<.001) increased, while the proportion of QFO (P<.001) decreased. The proportions of QP and QFO of the CCO remained unchanged from 30 to 38 weeks of gestation (Fig 6⇓). The proportion of QDA of the CCO did not change significantly during the second half of gestation. The proportion of RVCO of the CCO increased (P<.05) from 20 to 38 weeks of gestation, while the proportion of LVCO of the CCO decreased (P<.05). At 38 weeks of gestation, the proportion of RVCO of the total CCO (60%) was higher (P<.05) than that of LVCO (40%; Fig 6⇓).
QPi increased (P<.0001) from 20 to 30 weeks of gestation and then decreased (P<.01) from 30 to 38 weeks of gestation. QPi was greater at 38 weeks (P<.01) than at 20 weeks of gestation. QSi did not change significantly during the second half of pregnancy (Table 2⇓). The QPi-to-QSi ratio increased (P<.001) from 20 to 30 weeks of gestation and remained unchanged from 30 to 38 weeks (Table 2⇓ and Fig 7⇓). RPi decreased 1.5-fold from 20 to 30 weeks of gestation (P<.001); during the latter part of the third trimester, it again increased (P<.0001). RSi increased almost 2-fold during the second half of pregnancy (P<.001; Table 2⇓ and Fig 7⇓). The RPi-to-RSi ratio decreased significantly (P<.01) from 20 to 30 weeks of gestation and thereafter remained unchanged (Table 2⇓).
We found nearly a twofold increase in the proportion of QP compared with the CCO from 20 to 30 weeks of gestation (from 13% to 25%); during the last trimester, its proportion of the CCO remained unchanged. Our findings suggest that in the beginning of the second half of pregnancy, the QP represents ≈27% of the LVCO in the human fetus. During the third trimester, the proportion of QP of the LVCO is ≈50%, suggesting that the importance of QP as it contributes to LVCO increases with advancing gestation. Previously, St John Sutton et al4 estimated indirectly that the human fetal QP represents ≈20% of the CCO during the second half of pregnancy and suggested that this proportion does not change with advancing gestation. Our results, based on the direct measurement of the QP, support the concept that the proportion of QP of the human fetal CCO is clearly higher than suggested in previously published animal studies in which the proportion of QP of the CCO was estimated at <10%.8 9
The gestational period between 20 and 30 weeks is characterized by an almost 1.5-fold decrease in the RPi. This suggests that the growth of the lungs and the increase in the vasculature in the lung tissue are associated with the decrease in the pulmonary vascular resistance and an increase in the pulmonary blood flow during the end of the second trimester and in the beginning of the third trimester. This hypothesis is in agreement with our previous finding of decreasing pulmonary vascular impedance in the human fetus during this period of gestation.10 During the end of the third trimester, pulmonary vascular resistance increases while the growth of the lung continues. In fetal lambs, a similar increase in RPi from the end of the second trimester to term of gestation has been described.11 Animal studies have also revealed that the sensitivity of the pulmonary circulation to oxygen dramatically increases toward the term of pregnancy.11 Hypoxemia causes vasoconstriction in the fetal lamb pulmonary circulation, and the effect of hyperoxia is vasodilatation. During elevated oxygen tension, pulmonary blood flow increases in proportion to the increase in vessel density in the lung tissue; in fetal lambs near term, an increase in oxygen tension alone can induce the entire increase in pulmonary blood flow that normally occurs after the onset of breathing at birth.9 In other studies, it has been demonstrated that various factors, including prostaglandins, may affect fetal lamb pulmonary circulation.12 Our results suggest that the human fetal pulmonary circulation is affected by acquired vasoconstriction during the end of the third trimester, thus regulating the distribution of human fetal cardiac output from the pulmonary to the systemic circulation. These results also confirm our previous findings that showed that fetal pulmonary vascular impedance does not change during this period of gestation.10
The RPi-to-RSi ratio decreased significantly from 20 to 30 weeks of gestation, demonstrating the magnitude of the decrease in the pulmonary vascular resistance and its importance in the regulation of the distribution of fetal CCO. This ratio did not change significantly from 30 to 38 weeks, even though RPi increased again. This can be explained by RSi, which increased significantly from 30 to 38 weeks.
Volume blood flow across the foramen ovale is very difficult to assess directly. The cross-sectional area of the foramen ovale is difficult to calculate accurately, even though the foramen ovale diameters show linear increases with advancing gestation.13 The blood velocity waveform also is multiphasic during the cardiac cycle.13 14 However, QFO can be calculated by subtracting QP from LVCO. In our study, QP was based on the direct measurements, which minimized errors related to QFO calculation. The QFO increased fourfold, but its proportion of the CCO decreased significantly (from 34% to 19%) from 20 weeks to term of gestation. At 20 weeks of gestation, it represents ≈73% of the LVCO, but after 30 weeks of gestation, its proportion decreases to ≈50% of the LVCO. In the human fetus, the QFO has an important role because it has been shown that highly oxygenated blood returning from the placenta is directed mainly through the ductus venosus across the foramen ovale to the left atrium.15 Thus, the most oxygenated blood is supplied to the fetal coronary and cerebral circulations. According to our results, it can be assumed that during the third trimester, the foramen ovale may become restrictive and unable to increase its proportion of the CCO. This could support our finding of right ventricular dominance in the human fetus during the last trimester of pregnancy. It appears that after 20 weeks of gestation, right ventricular dominance persists and even increases toward the term. At 38 weeks of gestation, RVCO (60%) significantly exceeds LVCO (40%) as a proportion of the CCO, which may explain the appearance of disproportion between right and left ventricles in some third-trimester fetuses.
The methodological problems related to volumetric blood flow measurements in human fetuses are well known and have been discussed intensively.16 17 Volume blood flow measurements based on Doppler ultrasound have been demonstrated to be valid in both in vivo animal studies and in vitro studies.18 19 20 The human fetal cardiac output measurements at the level of AV and semilunar valves have been shown to correlate significantly.21 The intraobserver and interobserver variabilities of Doppler-determined volume flow across tricuspid valve have been <5%.20 Reed et al2 showed that maximal velocity tracings across cardiac valves could be obtained with a variation of <10%. The correlation coefficient between two observers for pulmonary arterial and aortic diameters was .98 and .96 for measurements of flow velocity integrals in the study of Kenny et al.1 Utilizing the recent advances in computed ultrasound and transducer technology, we attempted to calculate volume blood flow in the human fetus. To minimize the methodological errors, the angle between the vessel and the Doppler beam was kept at ≤15°. The vessel diameters were measured by using the well-established leading edge–to–leading edge method. We also calculated RVCO from PV and QP+QDA measurements, and these two independent calculations demonstrated an excellent correlation, thus proving the validity of our methodology. In our experience, this type of validation was not possible with earlier ultrasound equipment.
Human fetal arterial blood pressure has been measured at 20 weeks of gestation, and the mean carotid arterial blood pressure is ≈30 to 35 mm Hg.6 At 30 and 38 weeks, blood pressure values used in this study to represent fetal blood pressure were mean arterial blood pressure values measured in newborns born at the same gestational age.7 Mean blood pressure values in preterm newborns increase linearly with advancing gestational age, and it is reasonable to believe that this kind of linear increase in blood pressure occurs in human fetus. Before 20 weeks of gestation, human fetal mean arterial pressures have been shown to increase with increasing fetal weight.6 Invasive fetal lamb studies also have revealed a linear increase in fetal blood pressure.11 Although the absolute numeric blood pressure values in human fetuses may differ from those used in this study, direction and amplitude of changes in blood pressure are valid; thus, we believe that it is possible to evaluate the changes in the pulmonary and systemic vascular resistances. The ratio between weight-indexed pulmonary and systemic vascular resistances also eliminates the effect of blood pressure. Because the mean systemic and transpulmonary pressure gradients are equal in the fetus, the changes in the weight-indexed pulmonary blood flow during the second half of gestation while the weight-indexed systemic blood flow remains stable, as seen in the changes of the QPi/QSi, support the concept that the weight-indexed pulmonary vascular resistance decreases from 20 to 30 weeks of gestation and thereafter again increases. Another assumption we made in this study was that the fetal mean transpulmonary pressure gradient is equal to the mean systemic blood pressure. During pregnancy, the fetal DA is wide open, even though at term there may be a mild physiological constriction of the DA.22 This is also supported by our finding that the DA area became relatively smaller compared with the PV and branch pulmonary artery areas even though the volume blood flow was increasing during that period of gestation. Fetal lamb studies have shown that mean pulmonary arterial pressure is slightly higher (2 to 3 mm Hg) than mean systemic arterial pressure.11 23 When we subtract the left atrial pressure, which is estimated to be 2 to 3 mm Hg, from the mean pulmonary pressure, we obtain the estimated mean systemic pressure.
In conclusion, this study shows that it is possible to evaluate the CCO and its distribution in human fetuses during the second half of pregnancy noninvasively with state-of-the-art Doppler ultrasound techniques. An internal comparison of volume blood flow calculations showed good results with this method. The end of the second and the beginning of the third trimester are characterized by a decrease in pulmonary vascular resistance and an increase in the proportion of pulmonary blood flow of the fetal CCO. This proportion is higher than suggested in previous animal studies. The proportion of foramen ovale blood flow decreases. Later during the last trimester, pulmonary vascular resistance increases again. The proportion of the fetal CCO made up by the pulmonary blood flow is still ≈20% during this period and is the same as that of the foramen ovale blood flow. Right ventricular dominance persists and even increases toward the end of pregnancy. From this information, we conclude that the human fetal pulmonary circulation has an important role in the distribution of the fetal cardiac output.
Selected Abbreviations and Acronyms
|CCO||=||combined cardiac output|
|FHR||=||fetal heart rate|
|LPA||=||left pulmonary artery|
|LVCO||=||left ventricular cardiac output|
|LVSV||=||left ventricular stroke volume|
|RPA||=||right pulmonary artery|
|RVCO||=||right ventricular cardiac output|
|RVSV||=||right ventricular stroke volume|
- Received December 28, 1995.
- Revision received April 29, 1996.
- Accepted May 3, 1996.
- Copyright © 1996 by American Heart Association
Kenny JF, Plappert T, Doubilet P, Saltzman DH, Cartier M, Zollars L, Leatherman GF, St John Sutton MG. Changes in intracardiac blood flow velocities and right and left ventricular stroke volumes with gestational age in the normal human fetus: a prospective Doppler echocardiographic study. Circulation. 1986;74:1208-1216.
Reed KL, Meijboom EJ, Sahn DJ, Scagnelli SA, Valdes-Gruz LM, Shenker L. Cardiac Doppler flow velocities in human fetuses. Circulation. 1986;73:41-46.
St John Sutton M, Groves A, MacNeill A, Sharland G, Allan L. Assessment of changes in blood flow through the lungs and foramen ovale in the normal human fetus with gestational age: a prospective Doppler echocardiographic study. Br Heart J. 1994;71:232-237.
Versmold HT, Kitterman JA, Phibbs RH, Gregory GA, Tooley WH. Aortic blood pressure during the first 12 hours of life in infants with birth weight 610 to 4220 grams. Pediatrics. 1981;67:607-613.
Rudolph AM, Heymann MA. Circulatory changes during growth in the fetal lamb. Circ Res. 1970;26:289-299.
Morin FC III, Egan EA, Ferguson W, Lundgren CEG. Development of pulmonary vascular response to oxygen. Am J Physiol. 1988;254:H542-H546.
Morin FC III, Egan EA. Pulmonary hemodynamics in fetal lambs during development at normal and increased oxygen tension. J Appl Physiol. 1992;73:213-218.
Soyeur D, Schaaps JP, Kulbertus H. Pulsed Doppler assessment of fetal blood flow across the foramen ovale and pulmonary vascular bed. Eur Heart J. 1990;11:90. Abstract.
Schmidt KG, Di Tommaso M, Silverman NH, Rudolph AM. Doppler echocardiographic assessment of fetal descending aortic and umbilical blood flows: validation study in fetal lambs. Circulation. 1991;83:1731-1737.
Meijboom EJ, Horowitz S, Valdes-Cruz LM, Sahn DJ, Larson DF, Lima CO. A Doppler echocardiographic method for calculating volume flow across the tricuspid valve: correlative laboratory and clinical studies. Circulation. 1985;71:551-556.
Allan LD, Chita SK, Al-Ghazali W, Crawford DC, Tynan M. Doppler echocardiographic evaluation of the normal human fetal heart. Br Heart J. 1987;57:528-533.
Huhta JC, Moise KJ, Fisher DJ, Sharif DS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography. Circulation. 1987;75:406-412.
Abman SH, Accurso FJ. Acute effects of partial compression of ductus arteriosus on fetal pulmonary circulation. Am J Physiol. 1989;257:H626-H634.