Superior vena cava blood flow in normal and growth restricted fetuses

Assessing fetal well-being is crucial to enhance diagnosis, evaluate disease severity, optimize interventions when necessary, and improve perinatal outcomes. Doppler ultrasonography is widely used for noninvasive fetal surveillance, providing valuable insights into fetal physiology and hemodynamic changes in compromised fetuses. Intrauterine hypoxia initiates fetal adaptive hemodynamic responses, leading to increased blood supply to the brain and other vital organs at the expense of the placenta and lower body, a phenomenon known as "brain sparing". Currently, umbilical artery (UA) and middle cerebral artery (MCA) Doppler velocimetry, particularly the ratio of MCA pulsatility index (PI) and UA PI, is frequently employed to identify "brain sparing". However, it is important to note that the fetal response to hypoxia can impact both arterial circulation and venous return. We hypothesized that the quantification of SVC and umbilical vein (UV) blood flow could better reflect the circulatory balance between fetal cerebral and placental circulation.

The purpose of this thesis was to study fetal brain circulation in the second half of pregnancy using Doppler ultrasonography with a focus on cerebral venous return through superior vena cava (SVC) in normal and growth restricted fetuses with the anticipation that it may lead to the development of a new surveillance method for high-risk pregnancies.

Studies I-III were conducted on a low-risk pregnant population prospectively recruited at the Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway, from 2009 to 2012. These studies were part of a longitudinal research project evaluating fetal hemodynamics in the second half of pregnancy. A total of 142 uncomplicated singleton pregnancies between 20-40 weeks' gestation were included, and the participants underwent ultrasound examinations at approximately 4-weekly intervals. Fetal weight was estimated using biometry of the head, abdomen, and femur. Doppler velocity waveforms of SVC, MCA, UA, and UV were recorded and analyzed offline. The diameters of SVC and UV were measured using two-dimensional ultrasound images. Volume blood flow (Q) of the SVC and UV were quantified. The conventional pulsatility index (PI)-based cerebroplacental (CPR) and umbilicocerebral (UCR) ratios and Q-based indices of brain sparing, Q-CPR, and Q-UCR were calculated.

In Study I, we longitudinally investigated the ratio between cerebral and placental blood flow in the second half of normal pregnancies, quantifying volume blood flow in the SVC and UV during the second half of pregnancy. We established gestational age-specific reference intervals for Q-CPR and Q-UCR during the second half of pregnancy and found that there is a poor correlation and lack of agreement between PI-based and Q-based CPR and UCR. These results indicate that different physiological information may be obtained from venous and arterial circulation. Further investigation is necessary to see if these reference intervals are useful in fetal surveillance.

In Study II, we established longitudinal reference values for fetal SVC blood velocities and pulsatility index for veins (PIV) in the second half of pregnancy. An automated tracing of SVC waveforms using the software of ultrasound machine provided the peak systolic velocity (PSV), peak diastolic velocity (D), time-averaged maximum velocity (TAMAXV), time-averaged mean velocity (TAMEANV), and end-diastolic velocity during atrial contraction (A-velocity). The pulsatility index for veins (PIV) was calculated. Our findings showed that SVC velocities increased as pregnancy advanced, while PIV did not change significantly. Normative values of SVC velocities and PIV could be useful for fetal hemodynamic assessment in high-risk pregnancies.

In Study III, we aimed to quantify the proportion of fetal cardiac output (CO) distributed to the fetal brain and upper body during the second half of pregnancy using Doppler ultrasonography. To achieve this, we recorded the right and left cardiac ventricular outflow tract diameters and blood velocities and calculated the left, right, and combined cardiac output (CCO). We also estimated the SVC mean velocity from its TAMAXV and measured the SVC diameter to calculate the SVC volume blood flow (Q-SVC) using a mathematical equation, i.e., Q = mean velocity * cross-sectional area of the vessel. Q-SVC normalized for estimated fetal weight (Q-SVCw) was also calculated. The results showed that 10% of the SVC fraction of fetal CCO, calculated as (Q-SVC/CCO) * 100, was distributed to the brachio-cephalic circulation. This fraction remained constant during the latter half of pregnancy.

In study IV, we extended our research on SVC Doppler to pregnancies complicated by reduced fetal growth. We included 40 singleton pregnancies examined between 32+0 to 36+6 weeks of gestational age with estimated fetal weight (EFW)<10th percentile. We measured SVC blood flow velocities and diameter, PIV, as well as calculated Q-SVC, Q-SVCw, Q-CPR and Q-UCR. We then compared these variables to Z-scores of normal values published in our previous studies. We found significantly higher SVC diameter, Q-SVCw, Q-CPR, and significantly lower SVC velocities, PIV, and Q-UCR compared to normally grown fetuses. The volume blood flow (Q)- based indices of brain sparing were significantly altered in both small for gestational age (SGA) as well as growth restricted (FGR) fetuses. We demonstrated that an increase in SVC diameter rather than the blood flow velocity contributed to most of the increase in Q-SVCw.

In summary, we established normal reference ranges for fetal SVC volume blood flow, Doppler velocities, and PIV. We developed new volume blood flow-based indices of fetal brain sparing, constructed reference charts and demonstrated their usefulness in studying cerebral hemodynamic alterations in fetuses with late onset growth restriction. The findings of our studies may potentially have a wider application in future research and clinical practice.

List of scientific papers

I. Volume blood flow-based indices of fetal brain sparing in the second half of pregnancy: A longitudinal study. Stefopoulou M, Johnson J, Wilsgaard T, Lindgren P, Herling L, Kiserud T, Acharya G. Acta Obstet Gynecol Scand. 2020 Dec;99(12):1717-1727. Epub 2020 Jul 16.
https://doi.org/10.1111/aogs.13950

II. Reference ranges of fetal superior vena cava blood flow velocities and pulsatility index in the second half of pregnancy: a longitudinal study. Stefopoulou M, Herling L, Johnson J, Lindgren P, Kiserud T, Acharya G. BMC Pregnancy Childbirth. 2021 Feb 23;21(1):158. PMCID: PMC7901110
https://doi.org/10.1186/s12884-021-03635-6

III. Fetal superior vena cava blood flow and its fraction of cardiac output: A longitudinal ultrasound study in the second half of pregnancy. Stefopoulou M, Johnson J, Herling L, Lindgren P, Kiserud T, Acharya G. Front Pediatr. 2021 Jul 6;9:658502. PMCID: PMC8289903
https://doi.org/10.3389/fped.2021.658502

IV. Fetal superior vena cava blood flow and volume blood flow-based indices of brain sparing in fetuses with an estimated weight below the 10th percentile during the third trimester of pregnancy. Stefopoulou M, Johnson J, Lindgren P, Acharya G [Manuscript]