Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2024 May 22;19(5):e0302623. doi: 10.1371/journal.pone.0302623

Comparison of 2D and 3D oxygen-enhanced MRI of the placenta

Penny L Hubbard Cristinacce 1,*, Minal Patel 2, Alexander Oh 1, Josephine H Naish 1, Edward D Johnstone 2, Emma Ingram 2
Editor: Francesca Crovetto3
PMCID: PMC11111072  PMID: 38776318

Abstract

Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI) of the human placenta is potentially a sensitive marker of in vivo oxygenation. This methodological study shows that full coverage of the placenta is possible using 3D mapping of the change in longitudinal relaxation rate (ΔR1), in a group of healthy pregnant subjects breathing elevated levels of oxygen. Twelve pregnant subjects underwent a comparison of 2D and 3D OE-MRI. ΔR1 was mapped for a single 2D slice (ss-2D), a single matched-slice from the 3D volume (ss-3D) and the full 3D volume (vol-3D). The group-average median ΔR1 values for ss-3D (0.023 s-1) and vol-3D (0.022 s-1) do not differ significantly from ss-2D (0.020 s-1), when compared using a two-tailed paired t-test (ss-3D (p = 0.58) and vol-3D (p = 0.70)). However, median baseline T1 (T1b) for ss-2D was higher (1603 ms) than T1b for ss-3D (1540 ms, p = 0.07) and significantly higher than vol-3D (1515 ms, p = 0.02), when compared using a two-tailed paired t-test. In contrast with previous studies, no correlation of median ΔR1 with gestation age at scan for the normal group (N = 10) was observed for ss-2D, likely due to the smaller gestational range. Full volume OE-MRI maps reveal sensitivity to changes in ΔR1, with some participants showing an enhanced gradient in the intermediate space between the fetal and maternal sides of the placenta in the 3D data. This study shows that it is feasible to acquire whole placental volume OE-MRI data in women with healthy pregnancy.

Introduction

Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI) of the human placenta has shown promise in examining placental function [1, 2] and dysfunction [3] by being sensitive to in vivo oxygenation. Abnormalities of placental function can be associated with fetal growth restriction (FGR), which leads to increased neonatal morbidity and mortality [4, 5]. Non-invasive measurements of placental hypoxia, which is associated with peripheral hypovascularity and increased vascular resistance [6], have the potential to identify FGR independent of fetal size.

The spin-lattice relaxation time (T1) of tissue is shortened when a subject breathes an elevated concentration of oxygen due to the paramagnetic effect of the additional dissolved oxygen. This change can be quantitatively assessed by examining the change in R1 (where R1 = 1/T1), when a subject is switched from breathing air to 100% oxygen. Previous studies [1–3] have investigated this change by acquiring a single two-dimensional (2D) T1-weighted slice through the placenta. Here we investigate the feasibility of obtaining whole placental oxygenation maps using a three-dimensional (3D) volume acquisition.

The aim of the study was to investigate whether a 3D volume acquisition shows the same quantitative trends in R1 as a single 2D slice, and to assess whether the increased volume covered could offer more sensitivity to placental heterogeneity on a Philips 1.5 T MRI scanner. Full 3D coverage of the placenta may therefore allow a more comprehensive assessment of the placental oxygenation, as well as assessing known changes in gross tissue morphology.

Methods

Twelve subjects were recruited from St Mary’s Hospital, Manchester, following written informed consent (ethical approval REC:14/NW/0195 and 19/NW/0177) between 1st January 2018 to 31st December 2019. A summary of subject demographic and pregnancy outcome is given in Table 1. All subjects had normal uterine artery Doppler flow (pulsatility index <95th centile at 22–24 weeks) and normal umbilical artery Doppler flow (pulsatility index <95th percentile and positive end-diastolic flow) [7]. Pregnancies were subsequently classified as potentially abnormal based on an individualised birth ratio (IBR) <5th percentile (Gestation-related Optimal Weight [8]). Two women did not meet the outcome criteria for assignment to the normal group.

Table 1. Subject demographic and pregnancy outcomes.

Participant No. Maternal Age Range (years) BMI Gestational age at scan
(days)		 Placental position Delivery Gestation (days) Birth weight (g) IBR (centile)
1 31–35 24.3 196 Posterior 266 2730 10.8
2 16–20 29 169 Anterior 280 3289 19.7
3 26–30 36.9 176 Anterior 292 2900 1.3*
4 27–30 37.9 172 Posterior 265 2900 17
5 36–40 28.3 195 Posterior 270 3420 59.4
6 21–25 25 169 Anterior 282 3674 41
7 36–40 18.1 178 Posterior 273 3682 81
8 26–30 29.7 174 Posterior 236 2660 98
9 26–30 26.8 170 Anterior 275 2500 1.4*
10 31–35 17.4 176 Posterior 286 2950 12
11 26–30 21.3 106 Posterior 287 3106 15
12 31–35 21.5 194 Anterior 272 2830 7
Open in a new tab

*Abnormal based on an individualised birth ratio (IBR) <5th percentile.

Subjects were scanned using a 1.5T Philips Achieva MRI scanner (Philips Medical Systems Best, NL) whilst supine with a left lateral tilt, to reduce aortocaval compression by the gravid uterus. A cardiac-receiver coil was placed on the abdomen, covering the entire uterus. Non-rebreathing masks (Intersurgical, Wokingham, UK) delivered medical air or 100% oxygen at a flow rate of 15 L/min to the subjects and respiratory triggering was used to minimise motion from maternal breathing.

T2-weighted structural scans were used to determine the position of the placenta and plan the OE-MRI slices. Two inversion recovery OE-MRI protocols were performed: a 3D turbo-spin echo with half Fourier acquisition (3D-HASTE) for full placental coverage and a 2D turbo-spin echo (2D-TSE), as used in previous studies [2, 3]. The single 2D slice positioned perpendicular to the placenta at the level of the cord insertion. The orientation of the 3D-HASTE matched that of the 2D-TSE. For both OE-MRI protocols a T1 map was calculated using a set of inversion recovery images, followed by a dynamic series of T1-weighted images during which the gas supply to the subject is switched from medical air (21%) to 100% oxygen in order to determine ΔR1.

3D OE-MRI protocol

The majority of the data were acquired as follows: T1 mapping data for the 3D-HASTE acquisitions consisted of 5 separate acquisitions with inversion times (TI): 50, 300, 1100, 2000 ms and no inversion pulse (≈TR of 8 s, dependant on triggering), TE of 9 ms, 450 x 450 mm2 FOV, matrix size 176 x 176, voxel size 2.56 x 2.56 mm2, slice thickness 10 mm and 48 slices. Respiratory-triggered T1-weighted images were acquired dynamically at 40 time points with a temporal resolution of ~8 s (triggered off of every other breath), a TI of 1400 ms, with matching TE, FOV, matrix size, voxel size, slice thickness and number of slices. On the 10th dynamic, medical air was switched to 100% oxygen.

On completion of the 3D dynamic acquisition, the supply was switched back to medical air and a 2-minute interval was observed to return the oxygen levels to baseline.

Updated protocol:

In 2 data sets (subjects 11 and 12) the first TI, matrix size and voxel size were changed to match the 2D OE-MRI protocol below (60 ms, 128 x 128, 3.52 x 3.52 mm2).

2D OE-MRI protocol

T1 maps for the 2D-TSE acquisitions consisted of 5 inversions times (TI): 60, 300, 1100, 2000 ms and no TI. TR = TI + 8000 ms, TE of 5.4 ms, 450 x 450 mm2 FOV, matrix size 128 x 128, voxel size 3.52 x 3.52 mm2 and slice thickness 10 mm. Respiratory-triggered T1-weighted images were acquired dynamically at 40 time points with a temporal resolution of ~9.4 s and a TI of 1400 ms. On the 10th dynamic, medical air was switched to 100% oxygen.

Analysis

Data were analysed using in-house Python code. An ROI was defined on the TI = 300 ms image, which incorporated the entire placenta as observed on each slice. Care was taken on the fetal side of the placenta and at each end to exclude areas likely to be affected by motion. A T1 map was created by fitting a 3-parameter inversion recovery model to the data on a voxel-wise basis. The baseline/on air T1 (T1b) was used to calculate the change in R1 (ΔR1) for each dynamic in the T1-weighted series, as described elsewhere(1). The single slice from the 2D OE-MRI (ss-2D) was compared with a single matched slice from the 3D volume (ss-3D) and the entire volume (vol-3D). The slice was matched by using the 3D slice with the closest slice location, according to the DICOM header and checked visually.

Voxel-wise ΔR1 was calculated by taking the mean of the last 20 dynamics during the oxygen plateau and plotted as maps for both 2D and 3D data. Median and inter-quartile range (IQR) across the ROI of ΔR1 and T1b were calculated for each subject, to limit the influence of outliers in the voxel-wise maps. The correlation was calculated for median and IQR ΔR1 and T1b against gestational age at the scan, as in previous reports [1–3]. The significance of the correlation was measured by using the Pearson correlation coefficient and presented as r and P values.

Bland–Altman plots were produced to quantitatively assess the agreement between the two methods, with 95% confidence intervals (limits of agreement) calculated as the mean difference ± (1.96 × standard deviation of the difference). The ROIs for subjects identified as outliers on these plots were inspected visually on the dynamic data.

Example videos of the 3D ΔR1 maps can be found in the online supporting information (S4 File).

Two women who did not meet the outcome criteria for assignment to normal group (IBR <5th percentile) were removed from the gestational correlation analysis. All 12 subjects remained in all other comparisons.

Results

In Fig 1 the subject-average ΔR1 is plotted against dynamic number for the ss-2D data and the vol-3D data. For both, the signal increases from baseline after the oxygen concentration is increased (10th dynamic) and plateaus by the 20th dynamic image. The ss-2D and vol-3D curves plateaus around the same ΔR1 with a similar standard deviation on each dynamic ΔR1.

Fig 1. Mean (line) and standard deviation of the dynamic ΔR1 curves against dynamic image number for ss-2D (grey) compared with vol-3D (green).

Fig 1

Open in a new tab

Table 2 shows the group average median ΔR1 for ss-2D (0.020 s-1), ss-3D (0.023 s-1) and vol-3D (0.022 s-1) and that ss-3D (p = 0.58) and vol-3D (p = 0.70) do not differ significantly from ss-2D when compared using a two-tailed paired t-test. However, median T1b for ss-2D was higher (1603 ms) than T1b for ss-3D (1540 ms, p = 0.07) and significantly higher than vol-3D (1515 ms, p = 0.02), when compared using a two-tailed paired t-test. Correlation of median ΔR1 with gestation age at scan for the normal group (N = 10) revealed no trend with gestational age for ss-2D (p = 0.99), ss-3D (p = 0.14) and vol-3D (p = 0.24).

Table 2. Group average median and IQR ΔR1 and T1b values (12 subjects) and group average median and IQR ΔR1 and T1b values against gestational age at scan (10 subjects) for ss-2D, ss-3D and vol-3D.

ss-2D ss-3D vol-3D
median ΔR1, s-1 0.020
(0.004–0.038)		 0.023
(-0.006–0.047)		 0.022
(-0.003–0.048)
IQR ΔR1, s-1 0.024
(0.012–0.048)		 0.025
(0.015–0.045)		 0.027
(0.015–0.038)
median ΔR1 –gestation r 0.00
p 0.99		 r -0.25
p 0.14		 r -0.17
p 0.24
IQR ΔR1 –gestation r -0.18
p 0.23		 r -0.45
p 0.03 		r -0.64
p 0.005
median T1b, ms 1603
(1305–1679)		 1540
(1418–1693)		 1515
(1374–1723)
IQR T1b, ms 177
(86–275)		 196
(122–338)		 217
(152–340)
median T1b –gestation r 0.22
p 0.17		 r 0.11
p 0.77		 r 0.00
p 0.99
IQR T1b –gestation r 0.19
p 0.20		 r -0.39
p 0.05 		r -0.45
p 0.03
Open in a new tab

Table 2 also shows the inter-quartile range (IQR) of ΔR1, a measure of heterogeneity. The ss-2D values are not significantly different from ss-3D (p = 0.94) or vol-3D (p = 0.36) when compared using a two-tailed paired t-test. Correlation of IQR ΔR1 with gestation age at scan revealed lower values at longer gestation for the 3D data, ss-3D (p = 0.03) and vol-3D (p = 0.005).

A Bland–Altman plot shown in Fig 2 was used to investigate the agreement between ΔR1 for ss-2D with ss-3D and vol-3D for the individual subjects. The plots show no outliers for ss-2D and ss-3D or ss-2D and vol-3D. The 2D - 3D difference in ΔR1 is a smaller magnitude than the mean ΔR1. The average difference appears to decrease slightly as ΔR1 increases. Fig 3 show the Bland–Altman plots comparing the T1b values acquired from the 2D and 3D scans. The plots show a single outlier for ss-2D and ss-3D and no outliers for ss-2D and vol-3D. The mean difference shows the trend towards lower T1b values for ss-3D and vol-3D, compared with ss-2D.

Fig 2.

Fig 2

Open in a new tab

Bland–Altman plots of mean ΔR1 against the difference between 2D and 3D ΔR1 for (a) ss-2D and ss-3D and (b) ss-2D and vol-3D. The black dotted line represents the mean difference and the grey dotted lines the limits of agreement (95% confidence interval).

Fig 3.

Fig 3

Open in a new tab

Bland–Altman plots of mean T1b against the difference between 2D and 3D T1b for (a) ss-2D and ss-3D and (b) ss-2D and vol-3D. The black dotted line represents the mean difference and the grey dotted lines the limits of agreement (95% confidence interval).

Fig 4 shows maps comparing the voxel-wise ΔR1 for ss-2D and a matching slice from the 3D volume for an example anterior (Fig 4A and 4B) and posterior (Fig 4C and 4D) placenta. The 3D images exhibit similar features to the 2D maps for both of the placenta, however there are amplitude differences for the posterior placenta. Qualitatively, the ss-3D and vol-3D maps are less noisy and more blurred.

Fig 4.

Fig 4

Open in a new tab

Top: ΔR1 (s-1) maps of an example anterior placenta for (a) ss-2D and a matching (b) ss-3D; Bottom: ΔR1 (s-1) maps of an example posterior placenta for (a) ss-2D and a matching (b) ss-3D.

Discussion

This study shows that it is feasible to acquire whole placental volume OE-MRI data on a Philips 1.5 T MRI scanner. All scans were well tolerated by the pregnant subjects, even though increasing the coverage to 3D required the use of a cardiac-receiver coil in addition to the non-rebreathing mask.

There were no significant differences between median ΔR1 for the original single slice 2D protocol (ss-2D) compared with a matched single slice from the 3D data (ss-3D) or the full 3D volume (vol-3D), the individual difference between the 2D and 3D data was on the same order of magnitude as the group average and showed some scatter. All subjects fall within the limit of agreement (95% CI) on the ΔR1 Bland–Altman plots in Fig 2. Only subject 1 falls outside the limit for the ss-2D v ss-3D comparison of T1b (Fig 3). This subject has T1b in the normal range for ss-3D and vol-3D, but the 2D data shows a low median T1b (ss-2D 1305 ms compared to an average of 1603 ms).

Previous studies have shown a negative correlation of ΔR1 [1–3] and T1b [9, 10] with gestational age at scan. Here no correlation was significant in this study. However, this study included a relatively small group of subjects (10 compared with between 9 [2] and 41 [10]) and much smaller gestational window (169–196 days compared with up to 145–2671 days [2]). The study cohort was primarily chosen to allow the quality of the data acquired using the 3D protocol to be compared with that of the original 2D protocol, not to test for correlation with gestation. However, a negative trend in IQR ΔR1 and IQR T1b was apparent for 3D data (Table 2) corresponding to a reduction in heterogeneity with gestation. The two subjects that were removed from correlation of median R1 with gestational age at scan, due to an IBR < 5%, had relatively low or abnormal ΔR1. This is in qualitative agreement with the results of [3] (see maps in S4_File–subjects 5 and 9), however the number of subjects is too small to perform a quantitative comparison.

Fig 4 shows that the underlying images are of poorer quality for the 3D data (b and d) than for the 2D data (a and c), with more artefact and significant T2 blurring due to the long echo train and/or undersampling. However, similar features are observed for both the 2D and 3D ΔR1 maps. ΔR1 appears to be greater in the intermediate section of the placenta, with a decreasing gradient towards both the fetal and maternal sides. The 3D ΔR1 video maps in supporting information (S4_File) show that the gradient is observable throughout the extent of the placenta. The higher values of ΔR1 appear in the intermediate region where the villous tree exchanges oxygen between the maternal and fetal blood [11]. This gradient may be visible as a result of the higher signal-to-noise ratio of the 3D volume acquisition compared with the 2D, but it may be artificially enhanced by partial volume effects at the boundary between the placenta and the surrounding tissue due to image blurring. No statistically significant difference in the heterogeneity measurement IQR between the 2D and the 3D ΔR1 data was observed, however the correlation of IQR with gestational age shows a statistically significant decrease for both the ss-3D (p = 0.03) and vol-3D (p = 0.005), but not for ss-2D. This may be a result of an overall lower ΔR1 at later gestation leading to a smaller range or it may reflect a real increase in the homogeneity of oxygenation with increasing gestation to which the 3D data is sensitive.

There are number of limitations of the study. Firstly, the ROI was drawn on the TI = 300ms and applied to the dynamic series of data. The use of the 300ms data for region definition allowed the placenta to be differentiated more clearly, however any gross motion between this scan and the dynamic acquisition used to calculate ΔR1 could have a detrimental effect on the resulting maps and statistics. Secondly, unlike in previous OE-MRI studies [2, 3] where the ROI has been trimmed to only include voxels where placental tissue was present throughout the whole dynamic, the placental volume for each slice was included without trimming. Care was taken on the fetal side of the placenta to not include approximately one voxel around the amniotic sac to reduce the effects of fetal motion. Any significant motion was accepted as noise on the ΔR1 curve, with the intention of not unnecessarily removing placental tissue and biasing the analysis by drawing small ROIs. Thirdly, the 3D protocol was updated during the study to match the dimensions of the 2D protocol. This does not appear to have any significant effect on the quality of the data or the resulting maps, but the number of scans with the updated protocol is too small to test for any bias. The group average median ΔR1, with and without participants 11 and 12 (i.e. those scanned using the updated 3D OE protocol), differ by less than 0.002 s-1 and both ss-3D (p = 0.58) and vol-3D (p = 0.70) do not differ significantly from ss-2D when compared using a two-tailed paired t-test. This is similar to the data presented for all 12 participants. Finally, the slice matching to obtain the ss-3D data was performed by using the slice location from the DICOM header. This does not take into account gross motion between scans and is only an approximate due to even number of slices in 3D.

The aetiology of FGR is variable with specific phenotypes due to chromosomal, infectious, vascular disease and inflammatory-related causes. It is hoped that whole volume OE-MRI acquisition may allow for in utero placental phenotyping in FGR, thereby improving disease stratification, therapeutic intervention and outcome management. FGR placentas are known to have poor peripheral vascularisation and visible hypo-vascular regions [6]. Other gross lesions evident in maternal vascular malperfusion include placental hypoplasia, infarction and altered villous development [12]. These abnormalities are likely to lead to heterogeneity in the oxygenation across the placental volume that will be more readily observable when imaging the whole placental volume as opposed to a single central slice. A reliable measure of placental oxygenation across the entire placenta is a welcome addition to the MRI toolbox and could be utilised with other clinical markers and imaging to aid identification of the placental phenotype of FGR and improve fetal outcomes. Here we show that it is possible to obtain a measure of oxygenation via ΔR1 across the entire placenta on a Philips 1.5 T MRI scanner. The 3D OE-MRI measurement is sensitive to changes in placental oxygenation and allow mapping of the whole placental volume. Further work is necessary to implement this increased coverage on the scanners of other vendors.

Supporting information

S1 File. Fig 1 data.

Spreadsheet containing data for the ΔR1 curves in Fig 1.

(XLSX)

pone.0302623.s001.xlsx (275.4KB, xlsx)
S2 File. Figs 2 and 3 data.

Spreadsheet containing data for the Bland-Altman plots in Figs 2 and 3.

(XLSX)

pone.0302623.s002.xlsx (39.4KB, xlsx)
S3 File. Tables 1 and 2 data.

Spreadsheet containing data Tables 1 and 2.

(XLSX)

pone.0302623.s003.xlsx (84.6KB, xlsx)
S4 File. Fig 4.

Powerpoint file containing videos of ss-2D images and vol-3D videos of voxel-wise ΔR1 maps for all 12 pregnant subjects.

(PPTX)

pone.0302623.s004.pptx (16.5MB, pptx)

Acknowledgments

MRI scans were undertaken within Wolfson Molecular Imaging Centre. We thank radiographers and imaging centre staff for their support.

Data Availability

All relevant data and links to the code are within the manuscript and its Supporting Information files. Due to ethical concerns, supporting data cannot be made openly available. Further information about the data and conditions for access are available from the https://qbi-xnat.manchester.ac.uk repository at https://doi.org/10.48420/25266784 for researchers who meet the criteria for access to the data.

Funding Statement

This project was funded by Tommy's the baby charity with no specific code and supports numerous people/projects. (EDJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.Huen I, Morris DM, Wright C, Parker GJM, Sibley CP, Johnstone ED, et al. R1 and R2* changes in the human placenta in response to maternal oxygen challenge. Magn Reson Med. 2013;70(5):1427–33. doi: 10.1002/mrm.24581 [DOI] [PubMed] [Google Scholar]
  • 2.Ingram E, Hawkins L, Morris DM, Myers J, Sibley CP, Johnstone ED, et al. R1 changes in the human placenta at 3 T in response to a maternal oxygen challenge protocol. Placenta. 2016;39:151–3. doi: 10.1016/j.placenta.2016.01.016 [DOI] [PubMed] [Google Scholar]
  • 3.Ingram E, Morris D, Naish J, Myers J, Johnstone E. MR Imaging Measurements of Altered Placental Oxygenation in Pregnancies Complicated by Fetal Growth Restriction. Radiology. 2017;285(3):953–60. doi: 10.1148/radiol.2017162385 [DOI] [PubMed] [Google Scholar]
  • 4.Pallotto EK, Kilbride HW. Perinatal outcome and later implications of intrauterine growth restriction. Clin Obstet Gynecol. 2006;49(2):257–69. doi: 10.1097/00003081-200606000-00008 [DOI] [PubMed] [Google Scholar]
  • 5.Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. Am J Obstet Gynecol. 2000;182(1 I):198–206. doi: 10.1016/s0002-9378(00)70513-8 [DOI] [PubMed] [Google Scholar]
  • 6.Junaid TO, Brownbill P, Chalmers N, Johnstone ED, Aplin JD. Fetoplacental vascular alterations associated with fetal growth restriction. Placenta. 2014;35(10):808–15. doi: 10.1016/j.placenta.2014.07.013 [DOI] [PubMed] [Google Scholar]
  • 7.Gardosi J. Customized Fetal Growth Standards: Rationale and Clinical Application. Semin Perinatol. 2004;28(1):33–40. doi: 10.1053/j.semperi.2003.12.002 [DOI] [PubMed] [Google Scholar]
  • 8.Figueras F, Gratacós E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn Ther. 2014;36(2):86–98. doi: 10.1159/000357592 [DOI] [PubMed] [Google Scholar]
  • 9.Wright C, Morris DM, Baker PN, Sci B, Frcog DM, Crocker IP, et al. Magnetic Resonance Imaging Relaxation Time Measurements of the Placenta at 1.5 T. Placenta. 2011;32(12):1010–5. doi: 10.1016/j.placenta.2011.07.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Gowland PA, Freeman A, Issa B, Boulby P, Duncan KR, Moore RJ, et al. In vivo relaxation time measurements in the human placenta using echo planar imaging at 0.5 T. Magn Reson Imaging. 1998;16(3):241–7. doi: 10.1016/s0730-725x(97)00308-1 [DOI] [PubMed] [Google Scholar]
  • 11.Slator PJ, Hutter J, McCabe L, Gomes ADS, Price AN, Panagiotaki E, et al. Placenta microstructure and microcirculation imaging with diffusion MRI. Magn Reson Med. 2018;80(2):756–66. doi: 10.1002/mrm.27036 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Ernst LM. Maternal vascular malperfusion of the placental bed. APMIS. 2018;126(7):551–60. doi: 10.1111/apm.12833 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Francesca Crovetto

27 Dec 2023

PONE-D-23-27377Comparison of 2D and 3D oxygen-enhanced MRI of the placenta.PLOS ONE

Dear Dr. Hubbard Cristinacce,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Feb 10 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Francesca Crovetto

Academic Editor

PLOS ONE

Journal Requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Note from Emily Chenette, Editor in Chief of PLOS ONE, and Iain Hrynaszkiewicz, Director of Open Research Solutions at PLOS: Did you know that depositing data in a repository is associated with up to a 25% citation advantage (https://doi.org/10.1371/journal.pone.0230416)? If you’ve not already done so, consider depositing your raw data in a repository to ensure your work is read, appreciated and cited by the largest possible audience. You’ll also earn an Accessible Data icon on your published paper if you deposit your data in any participating repository (https://plos.org/open-science/open-data/#accessible-data).

3. Thank you for stating the following in the Acknowledgments Section of your manuscript: 

"This project was funded by Tommy's the baby charity. MRI scans were undertaken within Wolfson Molecular Imaging Centre."

We note that you have provided funding information that is currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. 

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: 

"This project was funded by Tommy's the baby charity with no specific code and supports numerous people/projects.  (EDJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. Thank you for stating the following in the Competing Interests section: 

"JHN has a shareholding and part time appointment at Bioxydyn Ltd, which provides oxygen-enhanced MRI services.

PLHC has worked as a consultant at Bioxydyn Ltd, which provides oxygen-enhanced MRI services.

The other authors have no relevant competing interests."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. 

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

5. We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see

https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

We will update your Data Availability statement on your behalf to reflect the information you provide.

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 

7. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

********** 

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

********** 

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

********** 

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

********** 

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript is written well, pointing out its limitations. Comparing the 2D and 3D OE-MRI is an interesting approach to add another possible placental oxygenation methodology. The authors provide complete data on all the 12 samples. In general, I agree with the authors' conclusion in the discussion. However, I would like to make a few comments.

1. Sample size

This is more a question than a comment. The authors have previously published data in OE-MRI and evaluated the feasibility of the 3T scanner (10.1016/j.placenta.2016.01.016), in which they included nine participants. In the current manuscript, they had 12 participants. Was there any sample size calculation or estimation for the present study? Could they obtain more participants from the second 3D protocol? If not, why?

2. Change of the 3D protocol

Sometimes it is inevitable to update a protocol in the middle of a study aiming for better results. However, it is difficult to defense this when there are different sample sizes in each protocol, such as in this study (10 vs 2). I understand that the sample size is limited, and it is challenging to prove it statistically. But I believe it is important to justify more about the effect of changing the protocol (lines 214-216).

3. Comments on the scanner feasibility

I find it a bit strange to read the comments about the feasibility of 3D OE-MRI on a Philips 1.5T MRI scanner in the first sentence of the discussion (line 167) and in the conclusion of the abstract (line 26) since it is not mentioned in the aim or introduction. It is more natural to say it is one of the aims and then comment on it in the discussion or the conclusion. Furthermore, the conclusion in the abstract and the main manuscript seem to have discrepancies.

Minor comment:

Line108: Something like “as in previous reports (1-3)” looks better.

********** 

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 May 22;19(5):e0302623. doi: 10.1371/journal.pone.0302623.r002

Author response to Decision Letter 0

27 Feb 2024

We thank the editor and reviewer for their input and useful suggestions. Please find our response to the points raise below:

Journal requirements

1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf [journals.plos.org] and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf [journals.plos.org]

The manuscript has now been amended to adhere to the PLOS ONE style guidance. Specifically, the title page has been amended, header sizes have been increased, figure referencing amended, and supporting information files renamed.

2) Note from Emily Chenette, Editor in Chief of PLOS ONE, and Iain Hrynaszkiewicz, Director of Open Research Solutions at PLOS: Did you know that depositing data in a repository is associated with up to a 25% citation advantage (https://doi.org/10.1371/journal.pone.0230416)? [doi.org] If you’ve not already done so, consider depositing your raw data in a repository to ensure your work is read, appreciated and cited by the largest possible audience. You’ll also earn an Accessible Data icon on your published paper if you deposit your data in any participating repository (https://plos.org/open-science/open-data/#accessible-data [plos.org]).

We have now uploaded the image data to our internal XNAT repository: https://qbi-xnat.manchester.ac.uk. To request access researchers should contact the corresponding author.

3) Thank you for stating the following in the Acknowledgments Section of your manuscript:

"This project was funded by Tommy's the baby charity. MRI scans were undertaken within Wolfson Molecular Imaging Centre."We note that you have provided funding information that is currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement.

The acknowledgements have been amended to remove reference to funding. We are happy with the current Funding Statement.

4) Thank you for stating the following in the Competing Interests section:

"JHN has a shareholding and part time appointment at Bioxydyn Ltd, which provides oxygen-enhanced MRI services.PLHC has worked as a consultant at Bioxydyn Ltd, which provides oxygen-enhanced MRI services. The other authors have no relevant competing interests."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). [journals.plos.org] If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

Please update the Competing Interests section to read: "JHN has a shareholding and part time appointment at Bioxydyn Ltd, which provides oxygen-enhanced MRI services. PLHC has worked as a consultant at Bioxydyn Ltd, which provides oxygen-enhanced MRI services. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors have no relevant competing interests."

5) We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. [journals.plos.org] Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see

https://journals.plos.org/plosone/s/recommended-repositories [journals.plos.org]. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. We will update your Data Availability statement on your behalf to reflect the information you provide.

Data contain potentially identifying or sensitive patient information of pregnant participants. The manuscript details the location of the scanning, the approximate date and the gestation of the pregnancy, and as such we are concerned about the ability of the participants to be identified via malicious data linking if imaging data are freely available. The Participant Information Sheet, agreed by the Ethics Committee, states that “Your information will only be used by organisations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research (https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/uk-policy-framework-health-social-care-research/).” As such, we feel it appropriate to check who is using the raw imaging data.

These images have now been uploaded to an internal XNAT repository. Requests for access should be sent to the corresponding author. All processed data which was used to create the figures in this manuscript is available as Supporting Information.

6) Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [journals.plos.org]

The supporting information file captions for now been included and file names amended accordingly.

7) Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

The references have been reviewed and doi added throughout.

Reviewer requirements

1) Sample size. This is more a question than a comment. The authors have previously published data in OE-MRI and evaluated the feasibility of the 3T scanner (10.1016/j.placenta.2016.01.016), in which they included nine participants. In the current manuscript, they had 12 participants. Was there any sample size calculation or estimation for the present study? Could they obtain more participants from the second 3D protocol? If not, why?

There was no sample size calculation performed for this study and the number of participants was limited by the timescale of the MSc students who were involved in the recruitment process. However, as the reviewer correctly states, previous studies used fewer participants, so we believe this number to be sufficient.

2) Change in the 3D protocol. Sometimes it is inevitable to update a protocol in the middle of a study aiming for better results. However, it is difficult to defense this when there are different sample sizes in each protocol, such as in this study (10 vs 2). I understand that the sample size is limited, and it is challenging to prove it statistically. But I believe it is important to justify more about the effect of changing the protocol (lines 214-216).

We agree that it isn’t ideal that the imaging protocol was changed. On inspection of the results with participants 11 and 12 removed (those with the updated 3D protocol), we observed a group average median �R1 for ss-2D (0.019 s-1), ss-3D (0.021 s-1) and vol-3D (0.021 s-1) and that ss-3D (p = 0.72) and vol-3D (p = 0.76) do not differ significantly from ss-2D when compared using a two-tailed paired t-test. This compares with the following (as stated in the manuscript):

“Table 2 shows the group average median �R1 for ss-2D (0.020 s-1), ss-3D (0.023 s-1) and vol-3D (0.022 s-1) and that ss-3D (p = 0.58) and vol-3D (p = 0.70) do not differ significantly from ss-2D when compared using a two-tailed paired t-test.”

We have added the following statement to the discussion of the manuscript:

“The group average median �R1, with and without participants 11 and 12 (i.e. those scanned using the updated 3D OE protocol), differ by less than 0.002 s-1 and both ss-3D (p = 0.58) and vol-3D (p = 0.70) do not differ significantly from ss-2D when compared using a two-tailed paired t-test. This is similar to the data presented for all 12 participants.”

3) Comments on the scanner feasibility. I find it a bit strange to read the comments about the feasibility of 3D OE-MRI on a Philips 1.5T MRI scanner in the first sentence of the discussion (line 167) and in the conclusion of the abstract (line 26) since it is not mentioned in the aim or introduction. It is more natural to say it is one of the aims and then comment on it in the discussion or the conclusion. Furthermore, the conclusion in the abstract and the main manuscript seem to have discrepancies.

We have looked to make the abstract, aims and discussion more coherent. The text “… placenta on a Philips 1.5 T MRI scanner. Further work is necessary to implement this increased coverage on the scanners of other vendors.” has been removed from the abstract and replaced with “…in women with healthy pregnancy”. The text has been added to line 48 of the introduction, as an aim, and to line 240 of the discussion, as future work. See highlight text in updated manuscript.

4) Minor comment:

Line108: Something like “as in previous reports (1-3)” looks better.

Minor comment addressed.

We hope the amendments described are satisfactory and reach the expected standard for the journal.

Decision Letter 1

Francesca Crovetto

9 Apr 2024

Comparison of 2D and 3D oxygen-enhanced MRI of the placenta.

PONE-D-23-27377R1

Dear Dr. Penny,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Francesca Crovetto

Academic Editor

PLOS ONE

Acceptance letter

Francesca Crovetto

1 May 2024

PONE-D-23-27377R1

PLOS ONE

Dear Dr. Hubbard Cristinacce,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Francesca Crovetto

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. Fig 1 data.

    Spreadsheet containing data for the ΔR1 curves in Fig 1.

    (XLSX)

    pone.0302623.s001.xlsx (275.4KB, xlsx)
    S2 File. Figs 2 and 3 data.

    Spreadsheet containing data for the Bland-Altman plots in Figs 2 and 3.

    (XLSX)

    pone.0302623.s002.xlsx (39.4KB, xlsx)
    S3 File. Tables 1 and 2 data.

    Spreadsheet containing data Tables 1 and 2.

    (XLSX)

    pone.0302623.s003.xlsx (84.6KB, xlsx)
    S4 File. Fig 4.

    Powerpoint file containing videos of ss-2D images and vol-3D videos of voxel-wise ΔR1 maps for all 12 pregnant subjects.

    (PPTX)

    pone.0302623.s004.pptx (16.5MB, pptx)

    Data Availability Statement

    All relevant data and links to the code are within the manuscript and its Supporting Information files. Due to ethical concerns, supporting data cannot be made openly available. Further information about the data and conditions for access are available from the https://qbi-xnat.manchester.ac.uk repository at https://doi.org/10.48420/25266784 for researchers who meet the criteria for access to the data.

    Articles from PLOS ONE are provided here courtesy of PLOS

    RESOURCES