Lactate detection in the brain of growth-restricted fetuses with magnetic resonance spectroscopy




Objective


The objective of the study was to determine the feasibility of detecting fetal brain lactate, a marker of fetal metabolic acidemia, using a noninvasive technique, proton magnetic resonance spectroscopy ( 1 H MRS), in intrauterine growth-restricted (IUGR) fetuses.


Study Design


In vivo human fetal brain lactate detection was determined by 1 H MRS in 5 fetuses with IUGR. Oxygenation and acid-base balance data were obtained at birth.


Results


1 H MRS analysis showed the presence of a lactate peak in the brain of the most severely affected IUGR fetus, with abnormal umbilical artery Doppler and fetal heart rate tracing. This finding was consistent with the low oxygen content and high lactic acid concentration observed in umbilical blood obtained at delivery.


Conclusion


1 H MRS allows the noninvasive detection of cerebral lactate in IUGR fetuses. Lactate detected by 1 H MRS may represent a possible marker of in utero cerebral injury or underperfusion.


Management and timing of delivery of intrauterine growth–restricted (IUGR) fetuses remains a central issue for obstetricians, because the risk of perinatal death has to be balanced with the cost of prematurity. Current available surveillance tests seem to have little impact on improving long-term neurodevelopmental outcome. Therefore, new markers of neurological damage should be sought, based on the understanding of the adaptive processes occurring in the human fetal brain during growth restriction.


Proton magnetic resonance spectroscopy ( 1 H MRS) is a noninvasive imaging technique that allows obtaining in vivo metabolic information from the brain. Brain 1 H MRS identifies several metabolites of biological importance, including lactate. It has been demonstrated that elevated levels of lactate detected by 1 H MRS in the brain of asphyxiated neonates are predictive of neurodevelopmental delay.


Plasma lactic acid concentration is indeed higher in IUGR fetuses with altered umbilical arterial Doppler velocimetry and abnormal fetal heart rate ; however, little is known about intrauterine changes in cerebral metabolism in IUGR fetuses.


In recent years, the fetal brain metabolic profile has been described in utero in uncomplicated pregnancy by 1 H MRS during the second and third trimesters. Such studies have failed to detect lactate in the normal fetal brain. However, several authors have recently suggested that the potential evidence of cerebral lactate is an indicator of altered fetal cerebral metabolism in pathological conditions.


In this study, we sought to measure fetal cerebral lactate using 1 H MRS to evaluate whether it could represent a marker of brain damage in IUGR fetuses.


Materials and Methods


Patients were enrolled at the Department of Mother Neonate and Child “L. Mangiagalli” of Milano, Italy. Magnetic resonance examinations were performed at the Magnetic Resonance Spectroscopy Unit Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, University of Milan, Milan, Italy. The study was approved by the Ethical Committee of the Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, and written informed consent was obtained from all patients.


Study population


We studied 5 singleton pregnancies complicated by IUGR between 28 and 37 weeks of gestation. Gestational age was calculated from the last menstrual period and confirmed by routine ultrasonography at 11-12 weeks of gestation.


We identified growth-restricted fetuses in utero through repeated longitudinal measurements that demonstrated a reduction in fetal growth velocity and further classified them according to umbilical arterial Doppler velocimetry and fetal heart rate (FHR) tracing. Specifically, IUGR was defined by measurements of abdominal circumferences below the 10th percentile of reference values for fetuses of similar ages together with a shift from the growth curve greater than 40 centiles. As an example, this represents a decrease from the 50th centile (measured at 20 weeks) to below the 10th centile (at the time of IUGR diagnosis). Growth restriction was confirmed at birth, if the neonatal weight was below the 10th percentile according to Italian standards for birth weight and gestational age. None of the fetuses were affected with abnormal karyotype, genetic syndromes, viral infection, or major malformations.


Antenatal fetal surveillance was conducted by multivessel arterial and venous Doppler velocimetry and FHR evaluation. Doppler waveforms were obtained from uterine arteries, umbilical artery (UA), middle cerebral artery (MCA), and ductus venosus. Uterine arteries Doppler velocimetry was considered altered, if the pulsatility index (PI) was 2 SDs above the mean for gestational age on both sides. UA Doppler waveform was considered abnormal, if the PI was 2 SDs above the mean for gestational age. End-diastolic velocity was classified as either present, absent, or reversed. In the MCA, a PI more than 2 SDs above the mean for gestational age was defined as brain sparing, indicating abnormally reduced impedance to flow in the cerebral circulation. Ductus venosus velocity during atrial systole was characterized as forward or absent/reversed.


FHR was considered abnormal, if at least 1 of the following patterns was present: less than 2 accelerations of the heart rate to an amplitude of 10 or more beats per minute lasting 15 seconds or more during a period of at least 30 minutes; variability of 5 or fewer beats per minute during a period of at least 60 minutes; and U-shaped (late) decelerations in the heart rate after Braxton Hicks contractions.


IUGR fetuses were classified into 3 groups of increasing clinical severity based on Doppler velocimetry of the umbilical artery and FHR as previously proposed. Briefly, type 1 IUGR showed both normal PI and FHR; type 2 IUGR had abnormal PI and normal FHR; and type 3 IUGR showed both abnormal parameters.


In the IUGR subjects, the concomitant presence of preeclampsia was defined as the onset of gestational hypertension and proteinuria after 20 weeks of gestation. Hypertension was defined as 2 or more recordings of a diastolic blood pressure of 90 mm Hg or more taken at least 4 hours apart. Proteinuria was considered as the excretion of 300 mg protein or more over a 24 hour period.


Preeclampsia was classified as severe, if 1 or more of the following criteria were present: blood pressure of 160/110 mm Hg or greater on 2 occasions on bed rest; proteinuria of 5 g or greater in a 24 hour urine specimen or 3 or greater on 2 random urine samples; oliguria; cerebral or visual disturbances; pulmonary edema or cyanosis; epigastric or right upper-quadrant pain; impaired liver function; and thrombocytopenia.


Severe preeclampsia was considered further complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) in the presence of hemolysis (lactate dehydrogenase >600 U/L), low platelets (<100,000/μL), and elevated liver enzymes (aspartate aminotransferase >70 U/L).


Timing and route of delivery were decided based on maternal and/or fetal parameters, according to our clinical protocol.


Days of hospitalization in the neonatal intensive care unit (NICU) and major neonatal complications were recorded.


MR procedures


Fetal brain MRI


All magnetic resonance (MR) examinations were performed on an MR system operating at 1.5 Tesla (Avanto, Siemens, Germany). No fetal sedation was used. Body-phased array coils were used in combination with spinal coils. The standard MR protocol included gradient-echo T1-weighted images following the 3 planes of the fetal head and single-shot T2-weighted images (half-Fourier acquisition, single-shot, turbo spin–echo [HASTE] sequence). Three-dimensional T2-weighted images (true fast imaging with steady precession, True-FISP sequence) were also acquired as needed.


Fetal localized brain magnetic resonance spectroscopy (MRS)


After the standard MRI protocol, to limit the time of the procedure as much as possible, the spectra were acquired with a single volume of interest (VOI) spin-echo sequence (PRESS). We located the VOI in the central brain areas (cerebral hemispheres; Figure 1 ), with the VOI centered on the midline to prevent any possible inclusion of scalp and extracranial tissues. To limit as much as possible any potential contamination from adjacent lipids during the acquisition of brain spectra, we ascertained whether the position of the fetal head was unchanged at the end of the 1 H MRS sequence by performing a rapid MRI (localizer) examination to obtain spectra with a sufficient signal-to-noise ratio (SNR) in the shortest time possible.




FIGURE 1


Location of the VOI for MRS

The parasagittal T2-weighted image, case 4, is shown.

MRS , magnetic resonance spectroscopy; VOI , volume of interest.

Cetin. Lactate detection in the human fetal brain. Am J Obstet Gynecol 2011.


Depending on the size of the fetal brain, the volume of the voxel was chosen to be between 10 and 24 cc to acquire MR spectra with sufficient SNR in a reasonable time. Sequences were performed with and without water saturation. The MRS parameters for the water suppressed spectra were as follows: echo time = 135 milliseconds, repetition time = 4000 milliseconds, 64 acquisitions. Total acquisition time (imaging and spectroscopy) was limited within 30 minutes in all cases. Data were processed with the use of jMRUI. The jMRUI is a software package used for the processing of MRS and MRSI data in the time domain ( http://www.mrui.uab.es ).


Data processing consisted of zero filling (2048 points), Gaussian filtering (4 Hz), Fourier transformation, and zero-order phase correction. No baseline correction was applied. The presence of the typical lactate signal, visible as an inverted doublet at the echo time used, was searched at 1.33 ppm.


Spectra were normalized to the N-acetylaspartate (NAA) peak. NAA is well detected and can be unambiguosly identified by MRS.


Oxygenation and acid-base balance at birth


Umbilical arterial and venous blood samples were obtained from a clamped segment of the cord immediately after delivery. Blood samples were collected into heparinized syringes and stored on ice until analyses. Fetal hemoglobin concentration (Hb), umbilical arterial and venous oxygen saturation, pH, pO2, pCO2, and lactate concentration were measured on a GEM Premier 3000 (Instrumentation Laboratory, Lexington, MA). Oxygen content was calculated according to the formula: O 2 content (millimoles) = Hb concentration (grams per liter) × O 2 saturation × 0.05982.


Statistical analysis


Data are presented as mean ± SD. Analyses were performed using SPSS Statistics Desktop (SPSS, Chicago, IL).




Results


Maternal age ranged between 29 and 35 years (mean, 31.8 ± 2.3 years) and maternal body mass index between 18 and 22 kg/m 2 (mean, 20.4 ± 1.5 kg/m 2 ). Tables 1 and 2 present the characteristics of the IUGR population at the time of MRS study and at the time of delivery, respectively. Gestational age at the time of MRS and at the time of delivery ranged from 28.2 to 37.0 weeks (mean, 32.6 ± 3.4 weeks) and from 28.5 to 38.5 weeks (mean, 33.5 ± 2.5 weeks), respectively. Time between MRS and delivery was 2-12 days (mean, 5 ± 4 days). Female-male sex ratio was 4:1.



TABLE 1

Gestational age, antenatal Doppler, and fetal heart rate of IUGR cases at the time of magnetic resonance spectroscopy
































































IUGR case no. GA at MRS, wks IUGR group Uterine arteries PI UA MCA DV AF FHR
1 37.0 1 Normal Normal Normal Normal Normal Reactive
2 35.3 1 Normal Normal Normal Normal Normal Reactive
3 32.6 2 Altered AEDF B.S. Normal Oligo Reactive
4 31.3 2 Altered PEDF B.S. Normal Oligo Reactive
5 28.2 3 Altered REDF B.S. Normal Oligo Altered

AEDF , absent-end diastolic flow; AF , amniotic fluid; B.S. , brain sparing; DV , ductus venosus; FHR , fetal heart rate; GA , gestational age; IUGR , intrauterine growth restriction; MCA , middle cerebral artery; MRS , magnetic resonance spectroscopy; oligo , oligohydramnios; PEDF , present-end diastolic flow; PI , pulsatility index; REDF , reverse-end diastolic flow; UA , umbilical artery.

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May 26, 2017 | Posted by in GYNECOLOGY | Comments Off on Lactate detection in the brain of growth-restricted fetuses with magnetic resonance spectroscopy

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