The hemodynamics of late-onset intrauterine growth restriction by MRI

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The hemodynamics of late-onset intrauterine growth restriction by MRI Meng Yuan Zhu, MS; Natasha Milligan, MS; Sarah Keating, MD; Rory Windrim, MD; Johannes Keunen, MD; Varsha Thakur, MD; Annika Ohman, MD; Sharon Portnoy, MS; John G. Sled, PhD; Edmond Kelly, MD; Shi-Joon Yoo, MD, PhD; Lars Gross-Wortmann, MD; Edgar Jaeggi, MD; Christopher K. Macgowan, PhD; John C. Kingdom, MD; Mike Seed, MBBS

BACKGROUND: Late-onset intrauterine growth restriction (IUGR)

results from a failure of the placenta to supply adequate nutrients and oxygen to the rapidly growing late-gestation fetus. Limitations in current monitoring methods present the need for additional techniques for more accurate diagnosis of IUGR in utero. New magnetic resonance imaging (MRI) technology now provides a noninvasive technique for fetal hemodynamic assessment, which could provide additional information over conventional Doppler methods. OBJECTIVE: The objective of the study was to use new MRI techniques to measure hemodynamic parameters and brain growth in late-onset IUGR fetuses. STUDY DESIGN: This was a prospective observational case control study to compare the flow and T2 of blood in the major fetal vessels and brain imaging findings using MRI. Indexed fetal oxygen delivery and consumption were calculated. Middle cerebral artery and umbilical artery pulsatility indexes and cerebroplacental ratio were acquired using ultrasound. A score of
2 of the 4 following parameters defined IUGR: (1) birthweight the third centile or less or 20% or greater drop in the centile in estimated fetal weight; (2) lowest cerebroplacental ratio after 30 weeks less than the fifth centile; (3) ponderal index < 2.2; and (4) placental histology meets predefined criteria for placental underperfusion. Measurements were compared between the 2 groups (Student t test) and correlations between parameters were analyzed (Pearson’s correlation). MRI measurements were compared with Doppler parameters for identifying IUGR defined by postnatal criteria (birthweight, placental histology, ponderal index) using receiver-operating characteristic curves.

I

ntrauterine growth restriction (IUGR) is associated with stillbirth and adverse perinatal outcomes.1,2 It is commonly the result of placental insufficiency.2 The conventional approach to identifying IUGR is through serial ultrasound-based measures of fetal growth and Doppler measurements in

Cite this article as: Zhu MY, Milligan N, Keating S, et al. The hemodynamics of late-onset intrauterine growth restriction by MRI. Am J Obstet Gynecol 2016;214: 367.e1-17. 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2015.10.004

RESULTS: We studied 14 IUGR and 26 non-IUGR fetuses at 35 weeks’ gestation. IUGR fetuses had lower umbilical vein (P ¼ .004) and pulmonary blood flow (P ¼ .01) and higher superior vena caval flow (P < .0001) by MRI. IUGR fetuses had asymmetric growth but smaller brains than normal fetuses (P < .0001). Newborns with IUGR also had smaller brains with otherwise essentially normal findings on MRI. Vessel T2s, oxygen delivery, oxygen consumption, middle cerebral artery pulsatility index, and cerebroplacental ratio were all significantly lower in IUGR fetuses, whereas there was no significant difference in umbilical artery pulsatility index. IUGR score correlated positively with superior vena caval flow and inversely with oxygen delivery, oxygen consumption, umbilical vein T2, and cerebroplacental ratio. Receiver-operating characteristic curves revealed equivalent performance of MRI and Doppler techniques in identifying IUGR that was defined based on postnatal parameters with superior vena caval flow area under the curve of 0.94 (95% confidence interval, 0.87e1.00) vs a cerebroplacental ratio area under the curve of 0.80 (95% confidence interval, 0.64e0.97). CONCLUSION: MRI revealed the expected circulatory redistribution in response to hypoxia in IUGR fetuses. The reduced oxygen delivery in IUGR fetuses indicated impaired placental oxygen transport, whereas reduced oxygen consumption presumably reflected metabolic adaptation to diminished substrate delivery, resulting in slower fetal growth. Despite brain sparing, placental insufficiency limits fetal brain growth. Superior vena caval flow and umbilical vein T2 by MRI may be useful new markers of late-onset IUGR. Key words: Doppler, fetus, intrauterine growth restriction, magnetic

resonance imaging, small for gestational age

the umbilical arteries (UAs). However, ultrasound-based fetal biometry and umbilical artery Doppler perform poorly in identifying IUGR in late gestation, with sensitivities ranging from 15% to 50% and false-positive rates in excess of 30%.3,4 Late-onset IUGR can be more accurately identified with cerebroplacental ratio (CPR), which can be especially helpful when IUGR occurs in fetuses with estimated fetal weights (EFW) above the 10th percentile.5,6 However, animal studies indicate that chronic fetal hypoxia ultimately reduces fetal oxygen consumption with normalization of fetal blood flow distribution and resolution of

the Doppler changes seen in acute hypoxia.7-9 This adaptive phenomenon could be an important limitation of middle cerebral artery (MCA) Doppler for the detection of fetuses at risk of abnormal brain development because of late-onset IUGR and highlights the need for more accurate tools for diagnosis of IUGR in utero. Invasive studies in animal models and human cordocentesis have demonstrated profound reductions in fetal blood oxygen saturation (SaO2) in IUGR fetuses.9,10 Fetal monitoring might therefore be improved by direct assessment of fetal oxygenation (ie, fetal oximetry). A new magnetic resonance

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imaging (MRI) technique for performing oximetry of fetal blood in vivo offers a safe alternative to invasive cordocentesis.11 Furthermore, the combination of magnetic resonance oximetry with magnetic resonance blood flow quantification could enhance the assessment of placental function by allowing the quantification of fetal oxygen delivery (DO2), whereas the calculation of oxygen consumption (VO2) and measurements of superior vena caval flow could help to characterize fetal metabolic and circulatory adaptations to hypoxia.12,13 Because the ultimate goal of fetal health assessment in late-onset IUGR is to optimize perinatal brain development, a more direct approach to assessing brain oxygenation may confer considerable potential benefits by facilitating more judicious timing of delivery.1,14

participate through the Obstetric Outpatient Clinic at Mount Sinai Hospital in Toronto from May 2013 to February 2015. Gestational age (GA) was determined from first-trimester crownrump length measurements. Pregnancies complicated by chronic maternal illnesses including diabetes, autoimmune disease, and hypertension were excluded. Fetuses with anemia, prenatally diagnosed congenital malformations, and genetic syndromes were also excluded.

Materials and Methods

Fetal body weight and brain weight

We conducted a prospective, crosssectional, case-control study comparing MRI and Doppler ultrasound measurements in fetuses with and without IUGR. Research MRI and ultrasound examinations were performed on a group of normal and suspected late-onset IUGR fetuses in the final weeks of pregnancy. Placental histology, anthropometric measurements, and brain MRI were performed soon after birth. Our recruitment included fetuses across a range of weight percentiles but was focused on small-for-gestational-age fetuses to provide a study group enriched for IUGR cases. A composite scoring system, based on both pre- and postnatal parameters, was used to define IUGR. We compared the performance of MRI and ultrasound parameters in terms of their concordance with postnatal evidence of IUGR.

Although there are no established reference ranges for fetal volume or fetal brain volume, these can be converted to body and brain weights and compared with GA-specific autopsy reference ranges.11,16-18 Figure 1 shows an example of fetal body (Figure 1A) and brain (Figure 1B) segmentation.

Participants

Magnetic resonance oximetry

This study was approved by the research ethics boards at the Hospital for Sick Children and Mount Sinai Hospital. Written consent was obtained from every subject. Pregnant women between 32þ0 and 41þ0 weeks’ gestation with singleton pregnancies were invited to

T2-based MR oximetry has been shown to be feasible in lamb fetuses and humans.21-23 In this study, we used a T2 preparation pulse sequence with an steady-state free precession readout and a nonrigid registration motion correction algorithm (Myomaps; Siemens

Imaging protocol

Healthcare, Erlangen, Germany) to perform T2 mapping in the major fetal vessels. Examples of T2 maps are shown in Figure 1, C and D. T2 relaxation time was measured from the T2 maps with a region of interest placed over the central 50% of the vessel in accordance with established criteria.24 We used a previously reported conversion from T2 to SaO2 (percentage O2) for adult blood according to our previously published technique.11,25 We determined the oxygen content of blood based on a GA appropriate estimation of fetal hemoglobin concentration.26

MRI imaging protocol

Each subject was scanned using the same imaging protocol according to our previously published technique.15 The scans were performed on a clinical 1.5T MRI system (Siemens Avanto, Erlangen, Germany). Details of the MRI sequence parameters are given in Appendices 1 and 2.

Blood flow quantification Phase-contrast (PC) MRI with metric optimized gating was used for the quantification of blood flow in the major fetal vessels.19,20 We prescribed acquisitions aligned perpendicular to the long axis of the descending aorta (DAo), superior vena cava (SVC), ascending aorta (AAo), main pulmonary artery (MPA), ductus arteriosus, umbilical vein (UV), and branch pulmonary arteries and indexed the measurements to EFW.

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Combined ventricular output (CVO), DO2, and O2 consumption (VO2) calculation CVO was estimated from the sum of the AAo and MPA flows plus an estimated coronary blood flow of 3% of the CVO based on lamb studies.12 Fetal DO2 and VO2 were calculated using the flow and T2 measurements according to our previously published technique.11 Fetal oxygen extraction fraction was calculated as VO2/DO2.

Doppler (UA and MCA) A research ultrasound was performed on the same day as the MRI, which included measurements of MCA and UA, pulsatility index, and CPR, and an estimation of fetal weight based on biparietal diameter, head circumference, abdominal circumference, and femur length. In addition to the research ultrasound, all clinical Doppler ultrasound measurements were gathered. CPR percentiles were determined based on reference data.27 IUGR diagnosis

We collected calculated the ponderal index and birthweight Z score for each newborn.28,29 The lowest GAappropriate percentile CPR after 30 weeks was recorded. Gross and histopathological examination of every placenta was performed by an expert in perinatal pathology (S.K.). In our IUGR scoring system, 1 point was allocated for a positive result in each of 4 categories, and a defined IUGR score of
2:

ajog.org 1. Birthweight third or less percentile or
20% drop in the percentile of ultrasound-based EFW over serial visits
2 weeks apart. 2. Ponderal index < 2.2 (grams per cubic centimeter). 3. Lowest CPR after 30 weeks less than the fifth percentile. 4. Placental histology meets predefined criteria for placental underperfusion (ie, placental weight less than the 10th percentile, multifocal infarction, or decidual vasculopathy).30

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FIGURE 1

Segmentations of fetal body and brain and T2 mapping of fetal vessels

When performing the receiveroperating characteristic (ROC) analysis for the MRI and Doppler parameters in identifying IUGR, only postnatal parameters (
2 of categories 1, 2, and 4 listed previously) were used to define IUGR to avoid bias toward CPR.

Statistical methods All measurements passed the omnibus normality test of D’Agostino et al31 except for the following: UA and pulmonary blood flow in the normal group and MPA T2 in the IUGR group. The initial analysis compared MRI and ultrasound parameters between IUGR and non-IUGR fetuses using a Student t test for normally distributed measurements or a Mann-Whitney test for measurements that were not normally distributed. We then used Pearson’s correlation to investigate the relationships between measurements. Linear regression and Bland-Altman plots were used to assess intra- and interobserver variability and reproducibility for MRI flow and T2 measurements. Finally, ROC curves were created to evaluate the performance of MRI and Doppler measurements in identifying IUGR. Statistical analysis was performed using GraphPad Prism 6.0e (GraphPad Inc, San Diego, CA). All values in the text are expressed as means  SDs. The results are expressed as means with SD and values of P < .05 were considered statistically significant.

Results Participants There were 69 women in late gestation who participated in the study. Among

A, Fetal body segmentation and volumetry of a MRI 3D-SSFP acquisition. B, Fetal brain segmentation and volumetry. C, T2 mapping of fetal MPA, AAO, and SVC; AAO is brighter (has higher T2) than MPA; SVC is the darkest. D, T2 mapping of UV and UA; UV is brighter than UA. AAO, ascending aorta; MPA, main pulmonary artery; MRI, magnetic resonance imaging; SSFP, steady-state free precession; SVC, superior vena cava; UA, umbilical artery; UV, umbilical vein. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

these, 29 subjects were excluded, 28 because the data obtained did not include all scoring parameters required

for group categorization and 1 because of unacceptable MRI image quality. The remaining 40 subjects were included in

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TABLE

Characteristics of normal and IUGR groups IUGR (n ¼ 14)

P values

GA at MRI scan, wks

35.9  0.9

35.4  2.4

.500

Maternal age, y

33.8  4.5

34  4

.700

Days from MRI to birth

11  13

21  10

.010a

Characteristics

EFW at MRI scan, kg EBW at MRI scan, g EBW Z-score

Normal (n ¼ 26)

2.8  0.3

1.9  0.6

300  29

.0001

249  55

0.02  0.86

e1.36  0.73

Neonatal brain MRI a

.005a < .0001a

EBW over EFW, %

10.9  1.0

13.8  2.3

.0004a

GA at birth, wks

39.6  1.1

37.0  2.8

.008a

Birthweight, kg Birthweight percentile

3.16  0.41 33  23

1.95  0.64

< .0001a

22

< .0001a

EFW, estimated fetal weight; GA, gestational age; IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging. a

Significantly different result. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

the analysis and all fetuses were born in good condition except 1 stillbirth of an IUGR fetus in the setting of preeclampsia. Subjects were classified based on our IUGR scoring system into 14 IUGR and 26 non-IUGR (clinical information is summarized in Appendix 3). A comparison of clinical characteristics between the 2 groups is shown in the Table. No significant differences were seen in either mean GA (P ¼ 0.6) or maternal age (P ¼ 0.7) at the time of MRI between the 2 groups. IUGR fetuses were born 2.4  0.8 weeks earlier than normal fetuses. The mean interval between MRI and birth was 11  13 days for IUGR fetuses and 21  10 days for normals (P ¼ .01).

Imaging results MRI growth findings

MRI-based EFW, birthweight, and birthweight percentile were significantly lower in IUGR fetuses. EFW by ultrasound and MRI were closely correlated (R2 ¼ 0.9, P < .0001). IUGR fetuses had lower EBW and brain weight Z score. We observed a higher ratio of EBW over EFW in the IUGR fetuses (P ¼ .0004). This impression of asymmetric growth restriction was confirmed by a higher ratio of the birth head circumference/ birthweight in IUGR newborns (P ¼ .0005).

MRI hemodynamic findings Approximately 20% of PC and T2 measurements needed to be repeated because of motion artefact. However, acceptable image quality was obtained in all but 1 subject for all vessels with an average scan duration of 45 minutes. We required 2-3 hours of postprocessing for each case. A high degree of intra- and interobserver agreement and reproducibility was found for MRI measurements (Appendice 4). Figure 2A shows a comparison of the MRI-measured major fetal vessel flows indexed to EFW. IUGR fetuses had significantly increased SVC flow (P < .0001) and ductus arteriosus flow (P ¼ .02) but decreased pulmonary blood flow (P ¼ 0.01) and UV flow (P ¼ .004) compared with normal fetuses. Figure 2B demonstrates significantly lower mean T2 values in all measured vessels in the IUGR fetuses. DO2 and VO2 were both lower in IUGR fetuses, as shown in Figure 3. Consequently, IUGR fetuses had significantly higher oxygen extraction fraction (40%  10%) than normal fetuses (34%  8%, P ¼ .03).

Doppler findings IUGR and normal fetuses were at a similar GA when the lowest CPR was recorded. Although a trend toward

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higher UA PI was seen in the IUGR fetuses, the difference was not statistically significant (P ¼ .08). By contrast, MCA PI (P ¼ .04) and CPR (P ¼ .005) were significantly lower in the IUGR group (Appendix 6).

Nine of 14 IUGR patients and 24 of 26 normal subjects underwent neonatal brain MRI, all of which were grossly normal. Three of 5 IUGR newborns that did not have neonatal MRI had normal cranial ultrasound findings. IUGR newborns had lower brain weight Z scores (P < .05). Four of the IUGR fetuses had diffuse excessive high signal (DEHSI) of the white matter, whereas none of the normal newborns had DEHSI. On magnetic resonance spectroscopy, approximately a third of the subjects in both groups had lactate in the basal ganglia. We found no difference in white matter apparent diffusion coefficient or N-acetyl aspartate to choline ratios between the 2 groups (Appendix 7).

Placental histology Twelve of 14 of the IUGR subjects met our histopathological criteria for IUGR. The 2 IUGR placentas that did not show the classical changes had mild placental abnormalities (1 had placental weight of the 10th to 25th percentile with mild dysmaturity of chorionic villi, and the other had increased villous vascularity with placental weight of the 25th to 50th percentile, whereas both had overcoiling of the umbilical cord). Of the 17 available non-IUGR placentas, 4 were below the 10th weight percentile, but none had multifocal infarction or decidual vasculopathy. Nearly all had subtle abnormal finding (eg, chorangiosis, villitis, villous dysmaturity, meconium staining, etc).

Correlations The relationships between the IUGR score and MRI parameters are shown in Figure 4. As IUGR score increased, MRI-measured UV flow, UV T2, and calculated DO2 and VO2 all decreased. Higher SVC flow was correlated with higher IUGR score (R2 ¼ 0.56,

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FIGURE 2

Flow and T2 relaxation time in major fetal vessels

A, MRI measured major vessel flows in the IUGR and normal fetuses. IUGR fetuses showed flow redistribution: high superior vena caval flow and low pulmonary blood flow. Low UV flow indicated possible placental insufficiency. The box and whisker plot shows medians and quartiles. Asterisk indicates significantly different result. Details are shown in Appendix 5. B, T2 relaxation time in major vessels in normal and IUGR fetuses. IUGR fetuses had lower T2 in all measured vessels. The box and whisker plot shows medians and quartiles. Asterisk indicates significantly different result. Details are shown in Appendix 5. AAo, ascending aorta; CVO, combined ventricular output; DA, ductus arteriosus; DAo, descending aorta; IUGR, intrauterine growth restriction; MPA, main pulmonary artery; MRI, magnetic resonance imaging; PBF, pulmonary blood flow; SVC, superior vena cava; UV, umbilical vein. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

P < .0001). In addition, the score correlated inversely with the fetal brain weight Z score, and positively with the weight percentage of the brain over the body. EBW was negatively correlated with SVC flow (R2 ¼ 0.25, P ¼ .0007) and positively correlated with UV T2 (R2 ¼ 0.22, P ¼ .002) and DO2 (R2 ¼ 0.14, P ¼ .01). EBW was also correlated with CPR (R2 ¼ 0.29, P ¼ .0004) and inversely correlated with UA PI (R2 ¼ 0.22, P ¼ .002). An inverse correlation was found between SVC flow and UV T2 (R2 ¼ 0.25, P ¼ .0007) (Figure 5). When the lowest CPR (including clinical data) was compared with MRI, the following correlations were found: as CPR decreased, so did UV T2 (R2 ¼ 0.12, P ¼ .03) and DO2 (R2 ¼ 0.31, P ¼ .0003), whereas SVC flow increased (R2 ¼ 0.26, P ¼ .0009). UA PI was positively correlated with SVC flow (R2 ¼ 0.18, P ¼ .006) and inversely related to UV T2 (R2 ¼ 0.16, P ¼ .01) and DO2 (R2 ¼ 0.29, P ¼ .0003).

MCA PI showed significant correlation with SVC flow (R2 ¼ 0.16, P ¼ .02). When MRI parameters were correlated with only the research Doppler parameters obtained on the same day as the MRI, the allocation of patients into IUGR or non-IUGR groups did not change. CPR correlated with UV flow but not with other MRI parameters. UA PI correlated with SVC flow (R2 ¼ 0.12, P ¼.03), DO2 (R2 ¼ 0.27, P ¼.001), UV T2 (R2 ¼ 0.11, P < .05), and UV flow (R2 ¼ 0.20, P ¼ .006).

FIGURE 3

Calculated VO2 and DO2 in IUGR and normal fetuses

Performance of MRI and Doppler by ROC curves When defining the IUGR patients solely based on postnatal evidence, there were 12 IUGR and 28 normal fetuses. Figure 6 illustrates the ROC plots for MRI and Doppler measurements for the identification of IUGR. Appendix 8 confirms that SVC flow had the highest area under the curve, although the differences between Doppler and MRI

IUGR fetuses had lower VO2 and DO2 than normal fetuses. The box and whisker plot shows medians and quartiles. Asterisk indicates significantly different result. Details are shown in Appendix 9. DO2, oxygen delivery; IUGR, intrauterine growth restriction; VO2, oxygen consumption. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

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FIGURE 4

The correlation of IUGR score with MRI parameters

Ambiguous IUGR score because of missing data was not included in this analysis. IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

parameters were not significant. The lowest CPR performed better than the CPR on the day of MRI at identifying IUGR.

FIGURE 5

Correlation between MRImeasured SVC flow and UV T2

Lower UV T2 is correlated with higher flow in the SVC. MRI, magnetic resonance imaging; SVC, superior vena cava; UV, umbilical vein. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

Comment In this study, MRI and ultrasound measurements of fetal hemodynamics and biometry in late-onset IUGR pregnancies were compared with normal fetuses. Our MRI parameters of fetal circulatory adaptation to placental insufficiency are concordant with conventional ultrasound measurements, especially CPR. Although the changes we observed in cerebral and placental vascular resistance are well documented by Doppler ultrasound in late-onset IUGR,3,6,32 our demonstration of fetal circulatory redistribution using MRI has previously been shown only in fetal lambs using invasive techniques.9 In the most severe examples of IUGR, the circulatory redistribution was dramatic, with an approximate doubling of cerebral blood flow (S01-S07) and halving of UV flow and SaO2 (S01, S06, S07, and S10), in keeping with fetal lamb studies.33 Increased SVC flow appears to be a very reliable indicator of IUGR.

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However, 5 fetuses (S08, S11-S14) had normal flow distributions by MRI and normal Dopplers but met the criteria of IUGR by the other 3 parameters. Importantly, these fetuses had reduced SaO2 and DO2 by MRI, confirming a hemodynamic basis for growth restriction and illustrating how fetal oximetry could improve the detection of IUGR. We hypothesize that in these fetuses, fetal VO2 was matched to DO2 through chronic adaptation to hypoxia through slowing of growth and resolution of any acute redistribution of blood flow. This switch from acute to chronic adaptation has previously been demonstrated in fetal lambs and may explain why CPR was noted to improve in half of the IUGR fetuses in our study.9,34 We conclude that normalization of CPR should not be regarded as evidence of the resolution of placental insufficiency and that MRI may be capable of identifying important placental insufficiency that might otherwise go

ajog.org undetected. However, the following considerations warrant further discussion.

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FIGURE 6

ROC curves of MRI and ultrasound measurements for identification of IUGR

Diagnosis of IUGR The absence of an agreed gold standard for IUGR diagnosis is a limitation of our study, and the IUGR scoring system we devised for this study has not been evaluated. Standard approaches to diagnosing IUGR include fetal Dopplers, ultrasound-derived fetal weight estimation, and postnatal anthropometric criteria.2,35 However, problems exist with each of these approaches. UA Doppler alone is relatively unreliable for recognizing late-onset IUGR, whereas only a proportion of late-onset IUGR fetuses display the most reliable Doppler measure of late-onset IUGR, namely an abnormal CPR.5,6 Fetal weight alone is a poor discriminator because small for gestational age is not equivalent to IUGR, and the potential for late gestation placental disease is implied by the known risk of stillbirth through a wide range of fetal weights.35,36 Although a decline in fetal growth from a higher initial rate is likely to be a reasonable marker of late-onset IUGR, a screening strategy using serial growth measurements poses substantial resource implications. Furthermore, in late gestation, serial measurements are unreliable when the interval between measurements is < 2 weeks.37 Postnatal criteria such as neonatal anthropometric measures and placental histopathology cannot be used to assist the diagnosis prospectively when the decisions need to be made regarding timing of delivery. However, they remain valuable for mechanistic studies, although some anthropometric measures such as neonatal length may suffer from poor reproducibility.35,38

Accuracy of MRI technique Fetal weight estimation by MRI in term infants is known to be more accurate than conventional ultrasound biometry techniques.39 PC blood flow quantification has been proven to be very accurate, with MPA and AAo measurements made in adult volunteers concordant within approximately 2%.40 PC flow

ROC curves of MRI and ultrasound-based measurements for identification of IUGR (score based on postnatal evidence) are shown. The SVC flow had a higher area under the curve than all ultrasound measurements, although the difference is not statistically significant. Details are shown in Appendix 7. CPR, cerebroplacental ratio; DO2, oxygen delivery; IUGR, intrauterine growth restriction; MCA, middle cerebral artery; MRI, magnetic resonance imaging; PI, pulsatility index; ROC, receiver-operating characteristic; SVC, superior vena cava; UA, umbilical artery; UV, umbilical vein. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

quantification in fetal vessels is challenging because of fetal motion and the small size of the vessels. However, the feasibility and accuracy of fetal PC with metric optimized gating has been established in phantoms and a human model.19,20,41 The accuracy of fetal MR blood T2 oximetry is supported by good agreement with blood gases in the vessels of children with congenital heart disease as well as in fetal lambs at baseline and during hypoxia, whereas the nonrigid registration motion correction algorithm we used for T2 mapping is likely to reduce artifacts resulting from fetal motion.11,12,21,42 However, the small size of the SVC and AAo are likely to result in those T2 measurements being

particularly susceptible to partial volume artifacts, and the conversion of T2 to SaO2 used in our study is based on adult blood and does not account for potential differences in the magnetic properties of fetal hemoglobin.24 Furthermore, the relationship between T2 and SaO2 is also influenced by hematocrit. Although GAappropriate estimations of hematocrit may be appropriate in the normal fetus, chronic fetal hypoxia is associated with polycythemia, which would shorten T2 and lead to an underestimated SaO2 (and therefore DO2).43,44 Despite these limitations, recent work on the magnetic properties of neonatal blood suggests that the assumptions we made in this study were valid, whereas recent evidence of the potential to

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correct T2-based oximetry for changes in hematocrit by combining T2 and T1 mapping may enhance the accuracy of fetal MR oximetry in the future.45,46 Nevertheless, without significant advances in magnetic resonance technology, technical limitations relating to the requirement for adequate spatial resolution and a signal to noise ratio are likely to continue to result in this type of MRI hemodynamic assessment being unsuitable for use in earlier gestations.

Conclusion Our new MRI technology provides a novel perspective on IUGR fetal cardiovascular physiology that is not accessible by conventional Doppler ultrasound and provides an additional facet to previously described MRI techniques for analyzing the morphology of placental disease.47 To fully assess the utility of MRI for diagnosing occult late-onset IUGR, further investigation with a larger sample size would be needed. Furthermore, the higher cost and limited availability of MRI will ensure that in the future, ultrasound is likely to remain the primary modality for detecting and monitoring late-onset IUGR. There remains interest in the possibility that some of the neurodevelopmental burden associated with late-onset IUGR could be averted with more timely delivery. In our study, the neonatal brain imaging was reassuring with respect to the impact of IUGR, and the absence of overt brain injury was in keeping with previous studies showing a low risk of cerebral palsy in smallfor-gestational-age fetuses with no associated birth defect.48,49 However, the increased incidence of DEHSI in our IUGR newborns is of uncertain significance, and abnormalities could have been present in the 5 of 14 subjects who did not undergo brain MRI. Our demonstration of impaired brain growth in IUGR fetuses despite brain sparing is in keeping with previous studies showing abnormal brain metabolism and growth in the setting of lateonset IUGR.50-53 These findings would therefore appear to support the future investigation of the neuroprotective potential of different management

strategies with regard to the timing of delivery in late-onset IUGR because previous studies have repeatedly demonstrated associations between developmental deficits and small for gestational age and smaller head size at birth.54-56 Although the potential benefit of early delivery from chronic fetal hypoxia needs to be weighed up carefully against the potential harms of iatrogenic late premature delivery for late-onset IUGR, an important first step will be more accurate detection of late-onset placental insufficiency. Even if the technique reported in this study remains primarily a research method, it may provide a helpful tool for future studies aimed at optimizing the timing of delivery in lateonset IUGR pregnancies. n References 1. Von Beckerath AK, Kollmann M, RotkyFast C, Karpf E, Lang U, Klaritsch P. Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction. Am J Obstet Gynecol 2013;208:e1-6. 2. Lausman A, Kingdom J. Intrauterine growth restriction: screening, diagnosis, and management. J Obstet Gynaecol Can 2013;35:741-8. 3. Backe B, Nakling J. Effectiveness of antenatal care: a population based study. Br J Obstet Gynaecol 1993;100:727-32. 4. Boers KE, Vijgen SMC, Bijlenga D, et al. Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT). BMJ 2010;341: c7087. 5. Oros D, Figueras F, Cruz-Martinez R, Meler E, Munmany M, Gratacos E. Longitudinal changes in uterine, umbilical and fetal cerebral Doppler indices in late-onset small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2011;37: 191-5. 6. DeVore GR. The importance of the cerebroplacental ratio in the evaluation of fetal wellbeing in SGA and AGA fetuses. Am J Obstet Gynecol 2015;213:5-15. 7. Pearce W. Hypoxic regulation of the fetal cerebral circulation. J Appl Physiol 2006;100: 731-8. 8. Richardson BS, Bocking AD. Metabolic and circulatory adaptations to chronic hypoxia in the fetus. Comp Biochem Physiol 1998;119: 717-23. 9. Poudel R, McMillen IC, Dunn SL, Zhang S, Morrison JL. Impact of chronic hypoxemia on blood flow to the brain, heart, and adrenal gland in the late-gestation IUGR sheep fetus. Am J Physiol Regul Integr Comp Physiol 2015;308: R151-62.

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ajog.org 10. Hecher K, Snijders RJ, Campbell S, Nicolaides KH. Fetal venous, intracardiac, and arterial blood flow measurements in intrauterine growth retardation: Relationship with fetal blood gases. Am J Obstet Gynecol 1995;173:10-5. 11. Sun L, Macgowan CK, Sled JG, et al. Reduced fetal cerebral oxygen consumption is associated with smaller brain size in fetuses with congenital heart disease. Circulation 2015;131: 1313-23. 12. Congenital diseases of the heart. In: Rudolph AM. Clinical-physiological considerations, 3rd ed. Chichester (United Kingdom): Wiley Blackwell; 2009. p. 2009. 13. Acharya G, Sitras V. Oxygen uptake of the human fetus at term. Acta Obstet Gynecol 2009;88:104-9. 14. Baschat AA. Neurodevelopment following fetal growth restriction and its relationship with antepartum parameters of placental dysfunction. Ultrasound Obstet Gynecol 2011;37:501-14. 15. Seed M. Advanced fetal cardiac MR imaging. In: Kline Fath B, Bahado Singh R, Bulas D, eds. Fundamental and advanced fetal imaging: ultrasound and MRI. Philadelphia, PA: Wolters Kluwer; 2015. 16. Baker P, Johnson I, Gowland P, et al. Fetal weight estimation by echo-planar magnetic resonance imaging. Lancet 1994;343:644-5. 17. Roelfsema NM, Hop WCJ, Boito SME, Wladimiroff JW. Three-dimensional sonographic measurement of normal fetal brain volume during the second half of pregnancy. Am J Obstet Gynecol 2004;190:275-80. 18. Guihard-Costa AM, Larroche JC, Droullé P, Narcy F. Fetal biometry. Growth charts for practical use in fetopathology and antenatal ultrasonography. Introduction. Fetal Diagn Ther 1995;10:211-78. 19. Seed M, van Amerom JFP, Yoo S-J, et al. Feasibility of quantification of the distribution of blood flow in the normal human fetal circulation using CMR: a cross-sectional study. J Cardiovasc Magn Reson 2012;14:79-90. 20. Prsa M, Sun L, Van Amerom J, et al. Reference ranges of blood flow in the major vessels of the normal human fetal circulation at term by phase contrast magnetic resonance imaging. Circulation 2014;7:663-70. 21. Wedegärtner U, Kooijman H, Yamamura J, et al. In vivo MRI measurement of fetal blood oxygen saturation in cardiac ventricles of fetal sheep: a feasibility study. Magn Reson Med 2010;64:32-41. 22. Wedegärtner U, Tchirikov M, Schäfer S, et al. Functional MR imaging: comparison of BOLD signal intensity changes in fetal organs with fetal and maternal oxyhemoglobin saturation during hypoxia in sheep. Radiology 2006;238:872-80. 23. Giri S, Chung Y-C, Merchant A, et al. T2 quantification for improved detection of myocardial edema. J Cardiovasc Magn Reson 2009;11:56. 24. Stainsby JA, Wright GA. Partial volume effects on vascular T2 measurements. Magn Reson Med 1998;40:494-9.

ajog.org 25. Wright GA, Hu BS, Macovski A. Estimating oxygen saturation of blood in vivo with MR imaging at 1.5 T. J Magn Reson Imaging 1991;1: 275-83. 26. Nicolaides KH, Clewell WH, Mibashan RS, Soothill PW, Rodeck CH, Campbell S. Fetal haemoglobin measurement in the assessment of red cell isoimmunisation. Lancet 1988;1: 1985-7. 27. Morales-Roselló J, Khalil A, Morlando M, Hervás-Marín D, Perales-Marín A. Doppler reference values of the fetal vertebral and middle cerebral arteries, at 19-41 weeks gestation. J Matern Fetal Neonatal Med 2015;28:338-43. 28. Kramer MS, Platt RW, Wen SW, et al. A new and improved polulation-based Canadian reference for birth weight for gestational age. Pediatrics 2001;108:E35. 29. Davies DP. Size at birth and growth in the first year of life of babies who are overweight and underweight at birth. Proc Nutr Soc 1980;39: 29-33. 30. Redline RW. Placental pathology: a systematic approach with clinical correlations. Placenta 2008;29(suppl):86-91. 31. D’Agostino RB, Belanger A, D’Agostino RB Sr, D’Agostino RB Jr. A suggestion for using powerful and informative tests of normality. Am Stat 1990;44:316-21. 32. Flood K, Unterscheider J, Daly S, et al. The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO Study. Am J Obstet Gynecol 2014;211:288. e1-5. 33. Cohn HE, Sacks EJ, Heymann MA, Rudolph AM. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol 1974;120:817-24. 34. Rurak DW, Richardson BS, Patrick JE, Carmichael L, Homan J. Oxygen consumption in the fetal lamb during sustained hypoxemia with progressive acidemia. Am J Physiol 1990;258: R1108-15. 35. Sifianou P. Approaching the diagnosis of growth-restricted neonates: a cohort study. BMC Pregnancy Childbirth 2010;10:6. 36. Moraitis AA, Wood AM, Flemin M, Smith GC. Birth weight percentile and the risk of term perinatal death. Obstet Gynecol 2014;124: 274-83. 37. Mongelli M, Ek S, Tambyrajia R. Screening for fetal growth restriction: a mathematical model of the effect of time interval and ultrasound error. Obstet Gynecol 1998;92:908-12. 38. Parra-Saavedra M, Crovetto F, Triunfo S, et al. Association of Doppler parameters with placental signs of underperfusion in late-onset

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SGA pregnancies. Ultrasound Obstet Gynecol 2014;44:330-7. 39. Zaretsky MV, Reichel TF, McIntire DD, Twickler DM. Comparison of magnetic resonance imaging to ultrasound in the estimation of birth weight at term. Am J Obstet Gynecol 2003;189:1017-20. 40. Lotz J, Meier C, Leppert A, Galanski M. Cardiovascular flow measurement with phasecontrast MR imaging: basic facts and implementation. Radiographics 2002;22:651-71. 41. Jansz MS, Seed M, Van Amerom JFP, et al. Metric optimized gating for fetal cardiac MRI. Magn Reson Med 2010;64:1304-14. 42. Nield LE, Qi X-LL, Valsangiacomo ER, et al. In vivo MRI measurement of blood oxygen saturation in children with congenital heart disease. Pediatr Radiol 2005;35:179-85. 43. Hermansen MC. Nucleated red blood cells in the fetus and newborn. Arch Dis Child Fetal Neonatal Ed 2001;84:F211-5. 44. Baschat AA, Gembruch U, Reiss I, Gortner L, Harman CR, Weiner CP. Neonatal nucleated red blood cell counts in growth-restricted fetuses: relationship to arterial and venous Doppler studies. Am J Obstet Gynecol 1999;181:190-5. 45. Liu P, Chalak LF, Krishnamurthy LC, et al. T1 and T2 values of human neonatal blood at 3 Tesla: dependence on hematocrit, oxygenation, and temperature. Magn Reson Med 2015 May 18. http://dx.doi.org/10.1002/mrm.25775. [Epub ahead of print]. 46. Portnoy S, Seed M, Zhu J, Sled JG, Macgowan CK. Combined T1 and T2 measurements for non-invasive evaluation of blood oxygen saturation and hematocrit. Presented at the 23rd Annual Meeting of the International Society of Magnetic Resonance in Medicine (abstract), May 2015, Toronto, Canada. 47. Damodaram M, Story L, Eixarch E, et al. Placental MRI in intrauterine fetal growth restriction. Placenta 2010;31:491-8. 48. Grobman WA, Lai Y, Rouse DJ, et al. The association of cerebral palsy and death with small-for-gestational-age birthweight in preterm neonates by individualized and populationbased percentiles. Am J Obstet Gynecol 2013;209:340.e1-5. 49. Blair EM, Nelson KB. Fetal growth restriction and risk of cerebral palsy in singletons born after at least 35 weeks’ gestation. Am J Obstet Gynecol 2015;212:520.e1-7. 50. Simões RV, Cruz-Lemini M, Bargalló N, Gratacós E, Sanz-Cortés M. Brain metabolite differences in one-year-old infants born small at term and association with neurodevelopmental outcome. Am J Obstet Gynecol 2015;213:210. e1-11.

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51. Sanz-Cortes M, Egaña-Ugrinovic G, Simoes RV, Vazquez L, Bargallo N, Gratacos E. Association of brain metabolism with sulcation and corpus callosum development assessed by MRI in late-onset small fetuses. Am J Obstet Gynecol 2015;212:804.e1-8. 52. Sanz-Cortes M, Egaña-Ugrinovic G, Zupan R, Figueras F, Gratacos E. Brainstem and cerebellar differences and their association with neurobehavior in term small-for-gestational-age fetuses assessed by fetal MRI. Am J Obstet Gynecol 2014;210:452.e1-8. 53. Egaña-Ugrinovic G, Sanz-Cortes M, Figueras F, Bargalló N, Gratacós E. Differences in cortical development assessed by fetal MRI in late-onset intrauterine growth restriction. Am J Obstet Gynecol 2013;209:126.e1-8. 54. Van Wyk L, Boers KE, van der Post JM, et al. Effects on (neuro)developmental and behavioral outcome at 2 years of age of induced labor compared with expectant management in intrauterine growth-restricted infants: long-term outcomes of the DIGITAT trial. Am J Obstet Gynecol 2012;206:e1-7. 55. Arcangeli T, Thilaganathan B, Hooper R, Khan KS, Bhide A. Neurodevelopmental delay in small babies at term: a systematic review. Ultrasound Obstet Gynecol 2012;40: 267-75. 56. Gale CR, O’Callaghan FJ, Bredow M, Martyn CN. The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years. Pediatrics 2006;118: 1486-92.

Author and article information From the Institute of Medical Science, University of Toronto, Toronto, ON, Canada (Ms Zhu and Dr Seed); Division of Cardiology (Ms Zhu, Dr Seed, and Drs Thakur, Ohman, Yoo, Gross-Wortmann, and Jaeggi) and Departments of Physiology and Experimental Medicine (Ms Portnoy and Drs Sled and Macgowan) and Division of Neonatology, Department of Paediatrics (Dr Kelley), Mount Sinai Hospital, University of Toronto, ON, Canada; Departments of Obstetrics and Gynecology (Ms Milligan and Drs Windrim and Kingdom) and Pathology and Laboratory Medicine (Dr Keating) and Division of Maternal-Fetal Medicine (Dr Keunen), Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada. Received July 27, 2015; revised Sept. 24, 2015; accepted Oct. 6, 2015. This study was supported by a Sickkids Foundation/ Canadian Institutes for Health Research new investigator research grant. The authors report no conflict of interest. Corresponding author: Mike Seed, MBBS. mike. [email protected]

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APPENDIX 1

Fetal MRI sequence protocol Slice Type Gating Resp. comp. TE, ms TR, ms NSA thick, mm Matrix size

Sequence

FOV, mm Temp. resol., ms Scan time, s

—

Breath hold

1.74

3.99

1

2

256  205  80 400

Phase contrast 2D

MOG

—

3.15

6.78

1

3

240  240

240

54

36

T2 mappingy

PG

—

1.15yy 3.97yy 1

6

224  181

350

4000

12

3D-SSFP

3D x

2D

—

13

FOV, field of view; MOG, metric optimized gating; MRI, magnetic resonance imaging; NSA, number of averages; PG, pseudo-gating; SSFP, steady-state free precession; TE, echo time; TR, repetition time. x

Velocity encoding sensitivity tailored according to vessel: 150 cm/s for arteries, 100 cm/s for veins and 50 cm/s for umbilical vein; y T2 mapping used 5 T2 preparation times, tailored to span the expected T2 of a given vessel (0 ms, 0.33*T2, 0.66*T2, 1.00*T2 and 1.33*T2), with 4000 ms of magnetization recovery between successive T2 preparations; yy Rapid imaging of the T2-prepared magnetization was performed using a single-shot SSFP sequence with the indicated TE/TR values. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

APPENDIX 2

Neonatal MRI sequence protocol Sequence

Type

TE, ms

Axial T1WI

2D

12

1500

Axial T2WI

2D

205

8620

Basal ganglia MRS

Single voxel

144

1500

120

Axial DWI (WM ADC)

2D

102

5200

4

4

Sag 3D-SSFP (brain volume)

3D

1

1

1.99

TR, ms

4.53

NSA

Slice thickness, mm

Matrix size

FOV, mm

1

4

256  205

140

99

1

4

320  256

140

96

240

186

128  128

240

152

192  192

200

66

—

17  19  12

Scan time, s

Mean WM ADC was calculated from regions of interest placed 14 regions of cerebral white matter. 2D, 2 dimensional; 3D, 3 dimensional; DWI, diffusion weighted imaging; MRI, magnetic resonance imaging; MRS, proton magnetic resonance spectroscopy; NSA, number of averages; SSFP, steadystate free precession; TE, echo time; TR, repetition time; WM ADC, white matter apparent diffusion coefficient. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

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APPENDIX 3

Delivery conditions of the IUGR subjects

Subject Mode of delivery

Length of stay in high Birth GA, Apgar score, Blood pH, intensity NICU, d Other clinical information wksþd 1 min/5 min UA/UV

S01

Failed IOL / Emg. CD

31þ6

9/9

e/7.23

S02

Sch. CD for IUGR

38þ3

8/9

7.15/7.26

S03

Sch. CD for IUGR

36þ2

4/7

S04

Failed IOL / Emg. CD

33þ5

S05

Emg. CD

Birthweight < third CPR< fifth PI < 2.2, Abnormal IUGR or 20th centile drop centile g/cm3 placenta score Y

N

Y

3

Supplemental O2, low lung V, hyperbillirubinemia

< Third

N

N

Y

2

7.17/7.25 80

Required resuscitation at birth, < Third mechanical ventricular hyperbillirubinemia, operated for PDA

Y

N

Y

3

9/9

7.2/7.27

8

None

< Third

Y

Y

Y

4

35þ4

9/9

7/22/7.3

8

None

< Third

Y

Y

Y

4

S06

Breech assisted vaginal delivery 33þ1

0/0

—

Autopsy consistent with IUGR and birth asphyxia

< Third

Y

N

Y

3

S07

Emg. CD due to nuchal cord

35þ1

9/9

7.17/7.22

3

None

< Third

Y

Y

Y

4

S08

Failed IOL / Emg. CD

38þ1

9/9

7.21/7.28

0

Hyperbillirubinemia

< Third

N

Y

Y

3

S09

IOL for IUGR

37þ5

8/9

7.2/7.28

1

None

< Third

Y

N

N

2

S10

Emg. CD for IUGR

37þ3

8/9

7.27/7.32

0

None

< Third

N

Y

Y

3

S11

Assisted SVD

40þ3

8/9

7.11/7.22

0

None

< Third

N

N

Y

2

S12

Failed IOL / Emg. CD

40þ5

9/9

7.18/7.27

0

None

< Third

N

N

Y

2

S13

Sch. CD for fibroids

39þ1

7/9

e/7.34

0

None

34 wks: 45th 39 wks: seventh

N

Y

N

2

S14

Sch. CD for breech presentation 39þ0

9/9

7.28/7.31

0

None

34 wks: 38th 39 wks: eighth

N

Y

Y

3

6

—

The IUGR group included the following: Subject S06 chose the mode of delivery and had a stillbirth. All others were born alive and well. S13 and S14 had birthweights greater than the third centile. Estimated fetal weight percentile of S13 was the 45th centile at 34 weeks and seventh at 39 weeks; S14’s estimated fetal weight percentile was 38th at 34 weeks and eighth at 39 weeks. The normal group included the following: 15 SVD, 4 IOL and then SVD, 2 scheduled cesarean delivery, 2 emergency cesarean delivery, and 3 assisted spontaneous vaginal delivery. All were born alive and well. None of the normal newborns were admitted to the NICU or had any neonatal medical problems. According to our IUGR scoring system, 13 fetuses scored 0 and 9 scored 1. Four fetuses had missing data on 1 parameter, but they scored 0 on all other 3 criteria. CPR, cerebroplacental ratio; Emg. CD, emergency cesarean delivery; GA, gestational age; IOL, induction of labor; IUGR, intrauterine growth restriction; N, no; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; PI, pulsatility index; Sch. CS, scheduled cesarean delivery; SVD, spontaneous vaginal delivery; V, volume; Y, yes. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

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< Third

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Incubated after birth

21

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Appendix 4 Inter- and intraobserver validations and reproducibility of measurements This appendix includes interobserver validation of MRI measurements and T2 measurements, intraobserver validation of MRI flow measurements and MRI T2 measurements, and reproducibility of MRI flow measurements and T2 measurements. AAo, ascending aorta; DA, ductus arteriosus; DAo, descending aorta; MPA, main pulmonary artery; MRI, magnetic resonance imaging; PBF, pulmonary blood flow; SVC, superior vena cava; UV, umbilical vein.

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APPENDIX 5

MRI flow and T2 measurements in major vessels in IUGR and non-IUGR fetuses Variables

CVO

MPA

AAo

SVC

DAo

UV

DA

PBF

251  42

204  38

128 35

253  43

134  29

179  34

71  34

518  112 295  54

196  54

211  57

251  66

105  26

234  72

43  22

.6

< .0001

Normal mean flow, mL/min per kilogram 463  54 IUGR mean flow, mL/min per kilogram P values

.1

.05

Reference Range, mL/min per kilogram27 (351e579) (169e353) (121e261) Normal mean T2, ms IUGR mean T2, ms

.9

(77e197) (160e344)

a

.004

125  23

88  14

104  17

192  29

78  22

92  31

69  18

77  19

145  31

.003a

.002a

.002a

(70e142)

(89e165)

(62e114)

.0002a

.02

a

(62e206) (109e265)

101  20

P values Reference range, ms29

a

.01a (0e160)

< .0001a

(72e138) (161e241)

IUGR fetuses had blood flow redistribution and lower T2 in all measured vessels. AAo, ascending aorta; CVO, combined ventricular output; DA, ductus arteriosus; DAo, descending aorta; MPA, main pulmonary artery; PBF, pulmonary blood flow; SVC, superior vena cava; UV, umbilical vein. a

Significantly different result. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

APPENDIX 6

Lowest CPR recorded (with associated UA and MCA PI) for normal and IUGR fetuses Variable

GA of measurement

UA PI

MCA PI

CPR

Normal

35.7  1.0

0.99  0.23

1.61  0.32

1.68  0.35

IUGR

36.3  3.1

1.22  0.38

1.39  0.29

1.24  0.44

P values

.5

.08

.04

a

.005a

Two groups had no difference in UA PI. IUGR fetuses had lower MCA PI and CPR. CPR, cerebroplacental ratio; GA, gestational age; IUGR, intrauterine growth restriction; MCA, middle cerebral artery; PI, pulsatility index; UA, umbilical artery. a

Significantly different result. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

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APPENDIX 7

MRI brain findings for IUGR and normal newborns P value

Variables

IUGR

Normal

Brain MRI GA, wks

40.4  2.1 (n ¼ 9)

40.1  1.4 (n ¼ 24)

Brain weight Z-score

e1.5  0.8 (n ¼ 9)

e0.8  1.0 (n ¼ 24)

DEHSI (incidences)

4 (n ¼ 9)

0 (n ¼ 24)

.0005a

WM NAA/Cho ratio

0.65  0.07 (n ¼ 8)

0.59  0.13 (n ¼ 21)

.06

Mean WM ADC

1736  146 (n ¼ 8)

1681  146 (n ¼ 24)

.40

.70 < .05a

Two groups had no difference in corrected gestational age when the brain MRI was performed. Brain Z-score was significantly lower in IUGR newborns, and the incidence of DEHSI is significantly higher in the IUGR newborns compared with normal newborns (by Fisher exact test). DEHSI, diffuse excessive high signal; GA, gestational age; IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging; WM ADC, white matter apparent diffusion coefficient; WM NAA/Ch, N-acetyl aspartate to choline. a

Significantly different result. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

APPENDIX 8

The areas under the ROC curves of MRI and ultrasound based measurements with 95% confidence intervals P value

AUC

95% confidence interval

CPR

0.80

0.64e0.97

.003a

MCA PI

0.80

0.64e0.95

.004a

UA PI

0.73

0.53e0.93

.020a

SVC flow

0.94

0.87e1.00

< .0001a

DO2

0.84

0.68e0.99

.0009a

UV T2

0.83

0.70e0.97

.0009a

AUC, area under the curve; CPR, cerebroplacental ratio; DO2, oxygen delivery; MCA, middle cerebral artery; PI, pulsatility index; SVC, superior vena cava; UV, umbilical vein. a

Significant result. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

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APPENDIX 9

Fetal oxygen consumption, oxygen delivery, and oxygen extraction fraction Variable

VO2, ml/min per kilogram

DO2, ml/min per kilogram

OEF, %

Normal

6.9  1.7

20.9  4.2

34  8

IUGR

5.5  1.7

13.9  4.2

40  10

P values

.02

a

< .0001

a

.03a

Oxygen extraction fraction was higher in IUGR fetuses. DO2, oxygen delivery; OEF, oxygen extraction fraction; VO2, oxygen consumption. a

Significantly different result. Zhu et al. MRI hemodynamics of IUGR. Am J Obstet Gynecol 2016.

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