The use of functional placental magnetic resonance imaging for assessment of the placenta after prolonged preterm rupture of the membranes in vivo: A pilot study

Abstract

Introduction:
Preterm prelabor rupture of membranes (PPROM) complicates 3% of pregnancies in the UK. Where delivery does not occur spontaneously, expectant management until 37 weeks of gestation is advocated, unless signs of maternal infection develop. However, clinical presentation of maternal infection can be a late sign and injurious fetal inflammatory responses may already have been activated. There is therefore a need for more sensitive markers to aid optimal timing of interventions. At present there is no non-invasive test in clinical practice to assess for infection in the fetal compartment and definitive diagnosis of chorioamnionitis is by histological assessment of the placenta after delivery. This study presents comprehensive functional placental magnetic resonance imaging (MRI) quantification, already used in other organ systems, to assess for infection/inflammation, in women with and without PPROM aiming to explore its use as a biomarker for inflammation within the feto-placental compartment in vivo.

Material and methods:
Placental MRI scans were performed in a cohort of 12 women (with one having two scans) with PPROM before 34 weeks of gestation (selected because of their high risk of infection), and in a control group of 87 women. Functional placental assessment was performed with magnetic resonance techniques sensitive to changes in the microstructure (diffusion) and tissue composition (relaxometry), with quantification performed both over the entire organ and in regions of interest between the basal and chorionic plate. Placental histology was analyzed after delivery where available.

Results:
Normative evolution of functional magnetic resonance biomarkers over gestation was studied. Cases of inflammation, as assessed by histological presence of chorioamnionitis, and umbilical cord vasculitis with or without funisitis, were associated with lower T2* (mean T2* at 30 weeks 50 ms compared with 58 ms in controls) and higher fractional anisotropy (mean at 30 weeks 0.55 compared with 0.45 in controls). These differences did not reach significance and there was substantial heterogeneity both in T2* and Apparent Diffusivitiy across the cohort.

Conclusions:
This first exploration of functional placental assessment in a cohort of women with PPROM demonstrates that functional placental MRI can reveal a range of placental changes associated with inflammatory processes. It is a promising tool to gain information and in the future to identify inflammation in vivo, and could therefore assist in improving optimal timing for interventions designed to prevent fetal injury.

Full text

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Acta Obstet Gynecol Scand. 2021;100:2244–2252.wileyonlinelibrary.com/journal/aogs
Received: 21 May 2021
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Revised: 18 August 2021
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Accepted: 31 August 2021
DOI : 10.1111/aogs.14267
ORIGINAL RESEARCH ARTICLE
The use of functional placental magnetic resonance imaging for
assessment of the placenta after prolonged preterm rupture of
the membranes in vivo: A pilot study
Jana Hutter1 | Laurence Jackson1 | Alison Ho1,2 | Carla Avena Zampieri1,2 |
Joseph V. Hajnal1 | Mudher Al- Adnani3 | Surabhi Nanda4 | Andrew H. Shennan2 |
Rachel M. Tribe2 | Deena Gibbons4 | Mary A. Rutherford1 | Lisa Story2,5
This is an op en access arti cle under the ter ms of the Creat ive Commo ns Attri bution License , which permit s use, dis tribu tion and reprod uction in any medium,
provide d the original wor k is properly cited.
© 2021 The Authors . Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & S ons Ltd on behalf of No rdic Federation of Societies of
Obstet rics and Gyneco logy (NFOG).
Abbreviations: ADC, app arent diffus ion coef ficient; FA, f ractional an isotropy; MRI , magnetic res onance i maging; PPROM , preter m prelabor rup ture of membran es; PTB, prete rm birth.
1Centre for Medical Engineering , King's
College L ondon , London, UK
2Depar tment of Women and Children's
Health , Schoo l of Life Course Sciences ,
King's College Lo ndon, L ondon , UK
3Cellular Pathology Department , St
Thomas' H ospit al, London, UK
4Peter Gorer Department of
Immunobiolog y, King's College Lo ndon,
London, UK
5Fetal Me dicine Unit, St Thomas' Hospital,
London, UK
Correspondence
Jana Hut ter, Centre for Medical
Enginee ring, K ing's College Lo ndon, 1st
Floor So uth Wing, St Thomas Hospital,
Westminster Bridge Road , SE17EH
London, UK.
Email: jana.hutter@kcl.ac.uk
Funding information
This work w as supported by the
Biomedical Research Centre at G uy's and
St Thomas’ NHS Foundation Trust, the
Nationa l Institute for Health Re search
NIHR and t he NIH (Hu man Placenta
Projec t [1U01HD087202- 01]). Dr Lisa
Story is f unded by the NIHR a s a Clinic al
Lectu rer for this project and J. H utter
by a Sir Henr y Wellcome Fellowsh ip
(201374/Z/16/Z) and a UKRI FLF
fellowship (MR/T018119/1).
Abstract
Introduction: Preterm prelabor rupture of membranes (PPROM) complicates 3% of
pregnancies in the UK. Where delivery does not occur spontaneously, expectant
management until 37 weeks of gestation is advocated, unless signs of maternal infec-
tion develop. However, clinical presentation of maternal infection can be a late sign
and injurious fetal inflammatory responses may already have been activated. There
is therefore a need for more sensitive markers to aid optimal timing of interventions.
At present there is no non- invasive test in clinical practice to assess for infection in
the fetal compartment and definitive diagnosis of chorioamnionitis is by histologi-
cal assessment of the placenta after delivery. This study presents comprehensive
functional placental magnetic resonance imaging (MRI) quantification, already used
in other organ systems, to assess for infection/inflammation, in women with and with-
out PPROM aiming to explore its use as a biomarker for inflammation within the feto-
placental compartment in vivo.
Material and methods: Placental MRI scans were performed in a cohort of 12 women
(with one having two scans) with PPROM before 34 weeks of gestation (selected be-
cause of their high risk of infection), and in a control group of 87 women. Functional
placental assessment was performed with magnetic resonance techniques sensitive
to changes in the microstructure (diffusion) and tissue composition (relaxometry),
with quantification performed both over the entire organ and in regions of interest
between the basal and chorionic plate. Placental histology was analyzed after delivery
where available.
Results: Normative evolution of functional magnetic resonance biomarkers over ges-
tation was studied. Cases of inflammation, as assessed by histological presence of cho-
rioamnionitis, and umbilical cord vasculitis with or without funisitis, were associated

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HUTT ER ET al.
1 | INTRODUC TION
Preterm birth (PTB) is defined as deliver y before 37 weeks of gesta-
tion and occ urs in up to 8% of pr egnan ci es1 in th e UK. It is asso ci at ed
with fetal morbidit y and mortality both in the neonatal period and
beyond, particularly at very preterm gestations and where placen-
tal inflammation (chorioamnionitis) is present2. As a result, PTB also
constitutes an important burden for public health.3 Approximately
40% of cases of PTB are associated with preterm prelabor rupture
of the membranes (PPROM).4 PPROM before 37 weeks of gesta-
tion complicates 3% of all pregnancies in the UK .5 The median time
between membrane rupture and delivery in these cases is 7 days
but where delivery has not occurred expectant management is ad-
vocated in the absence of signs of maternal infection, to reduce the
morbidity and mortality associated with preterm deliver y before
37 weeks.6 – 8
Infection is a significant complication of expec tant management,
and can often occur in the fetus in the absence of clinical signs in the
mother.9 Neonatal morbidity, including sepsis, cystic periventricular
leukomalacia, intraventricular hemorrhage, and later development
of cerebral palsy, are significantly higher among pregnancies with
PPROM complicated by infection as assessed by chorioamnionitis
in the placenta after delivery.5,10,11 Chorioamnionitis is also known
to alter the immune profile of the infant at birth.12 Up to 71% of
cases with PPROM have histological evidence of chorioamnionitis
on placental analysis, par ticularly at early gestations, yet 30% can be
subclinical, without signs of maternal fever, fetal tachycardia, uter-
ine tenderness or purulent discharge.9 Expectant management may
therefore increase risks for both mother and baby if signs of infec-
tion are not overt.
Placental histopathological assessment only allows a retrospec-
tive diagnosis of chorioamnionitis and does not facilitate timely an-
tenatal intervention such as administration of corticosteroids and/
or early delivery or in utero transfer. Advanced functional magnetic
resonance imaging (MRI) techniques provide a means of quantifying
tissue changes and have been used in the gastrointestinal tract1 3,14
and heart15 to discriminate between acute and chronic phases of
inflammation in vivo. Placental MRI has been pioneered in normal
pregnancies during hyperoxygenation and normox ygenation16 in the
assessment of conditions including fetal growth restriction17 and
preeclampsia18 revealing distinct phenotypes. Techniques include
magnetic resonance relaxometry, targeting the paramagnetic prop-
erties of deoxygenated hemoglobin to gain insights into the oxygen
concentration,18,19 diffusion MRI to identif y microstructural changes
to the villous trees and flow in the inter- villous spaces,20 as well as
combinations of approaches leading to more distinct descriptions of
placental compartmental properties.21,22
This study aimed to assess the feasibility of MRI as a non- invasive
antenatal assessment tool for evaluating intrauterine infection
based on placental assessment. This could prove invaluable informa-
tion for bot h the timing of de li ve r y, and ant en at al inter venti on s, wi th
the ultimate aim to minimize the morbidity/mortality associated with
infection/inflammation in the context of PTB.
2 | MATERIAL AND METHODS
2.1 | Cohorts and clinical data collection
Women with PPROM before 34 weeks of gestation were recruited
prospec tively from a tertiary referral hospital in South London
(Table 1).
with lower T2* (mean T2* at 30 weeks 50 ms compared with 58 ms in controls) and
higher fractional anisotropy (mean at 30 weeks 0.55 compared with 0.45 in controls).
These differences did not reach significance and there was substantial heterogeneity
both in T2* and Apparent Diffusivitiy across the cohort.
Conclusions: This first exploration of functional placental assessment in a cohort of
women with PPROM demonstrates that functional placental MRI can reveal a range
of placental changes associated with inflammatory processes. It is a promising tool to
gain information and in the future to identify inflammation in vivo, and could therefore
assist in improving optimal timing for inter ventions designed to prevent fetal injury.
KEYWORDS
chorioamnionitis, histopathology, inflammation, magnetic resonance imaging, placenta,
preterm prelabor rupture of membranes, preterm birth
Key Message
This study proposes novel functional MRI methods as
a biomarker to assess signs of inflammation within the
human placenta revealing a distinct phenot ype in women
with preterm prelabor rupture of membranes and placental
inflammation.

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Preterm prelabor rupture of membranes was confirmed on
clinical grounds using speculum examination and biochemically
using the rupture of membrane (ROM) test (ROM Plus® Rupture of
Membranes Test; Clinical Innovations) when consented. Inclusion
criteria included 16– 34 weeks of gestation, singleton pregnancy, not
in active labor, and ability to give informed consent. Exclusion crite-
ria were: diagnosis of gestational diabetes, preeclampsia, chromo-
somal abnormalities, any other diagnosis associated with placental
insu ff iciency, maternal body mass inde x gre ate r than 35 kg/m2, mul-
tiple pregnancies, metallic implants, and claustrophobia. Following
assessment of eligibility, writ ten consent was obtained and an MRI
scan was performed on a 3T MRI system (Phillips Best).
One participant, scanned because of suspected PPROM, did not
have a confirmed ROM test, had normal amniotic fluid at subsequent
scans throughout and did not continue to leak fluid vaginally, so the
decision was made to exclude her from any subsequent analysis.
A control cohor t was selected from existing data sets from three
studies (19- SS- 0032, 19/LO/0852, and 14/LO/1169) where women
had been scanned between 16 and 39 weeks of gestation and de-
livery had occurred after 37 weeks of gestation, with a neonatal
birthweight above the third centile. There was no evidence of hy-
pertensive disorders in pregnancy in this control cohort.
The number of days from MRI scan to delivery (see Figure 1A
for a timeline), pregnancy outcome including gestation, weight
at birth, fetal sex, Apgar scores at 5 minutes, and postnatal and
maternal complications were recorded. Placentae were analyzed
histopathologically using a structured assessment23 and assessed
both macroscopically and microscopically. Evidence for chorioamni-
onitis, umbilical cord vasculitis, funisitis, chorionic plate fetal vessel
vasculitis, presence of thrombi, villitis, infarc tion, fibrin deposition,
and maturation of the villi was recorded wherever available (see
Figure 1B for the locations).
2.2 | MRI assessment
Women were scanned in a clinical 3T scanner using a 32- channel car-
diac coil in supine position with adequate cushioning and positioning.
Regular verbal communication was maintained throughout the scan.
The scan time was limited to 60 minutes in blocks of 30 minutes with a
break of fered in the middle. Continuous monitoring of oxygen satura-
tions, hear t rate and blood pressure (in 10- min ute intervals) was und er-
taken. Optimizatio n of all sequence s was per forme d previously to keep
the acoustic noise below 98 db(A). Following localizer and preparation
scans, anatomical scans of the entire uterus were performed using
two- dimensional TSE sequences in five orientations. A B0 map was
acquired and manual shimming using an in- house tool was performed
focusing on the placenta.24 Then, a two- dimensional multi- slice multi-
echo gra di ent- ech o ec ho pla nar imagi ng seq uence with four ech o ti me s
was acquired to allow T2* mapping with the following parameters:
TAB LE 1 Patient cohort overview
PPROM Control
GA scan (we eks) 27. 58 ± 2.69 (24.15– 33.00) 29.93 ± 4.40 (21.71– 38.29)
Maternal age (years) 32.48 ± 0.63 (31.85– 33.12) 34.00 ± 3.70 (25.01– 45.13)
GA delivery (weeks) 31.46 ± 2.94 (28.14– 37.71) 39.96 ± 1.28 (36.86– 42.43)
BW deliver y (grams) 1663.75 ± 533.33 (1050.00– 2600.00) 3393.37 ± 446.10 (2026.00– 4400.00)
Note: Only the second scan from the participant scanned twice was included in the s tatis tics presented here. The numbers indicate mean ± SD.
Abbreviations: BW, birthweight; GA , gest ational age; PPROM, preterm prelab or rupture of membranes.
FIGURE 1 Schemata of (A) the timelines involved and (B) the localization of relevant inflammatory processes in the placenta. GA,
gestational age; MRI, magnetic resonance imaging; ROM, rupture of the membranes

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HUTT ER ET al.
field- of- view = 360 mm × (320– 400) mm × (60– 120) mm, resolution
3- mm isotropic, repetition time = 2.6 s, echo times between 11.6 and
182 ms, 1– 2 dynamics. A combined diffusion- weighted relaxometry
scan with optimized b- values, b- vectors and four echo times as previ-
ously described19,2 2 was obtained.
2.3 | Data processing
All MRI data sets were assessed for overt fetal pathology. Placental
data from all three considered functional modalities was manually
segmented by two experienced placenta observers (authors JH,
AH) keeping a conservative margin to the chorionic and basal plate
to avoid inclusion of any non- placental maternal tissue or amniotic
fluid. These segmentations included the entire placental paren-
chyma for the multi- echo gradient echo scan and the diffusion MRI.
Mono- exponential decay models were fitted to the data acquired
for T2* maps using an in- house py thon script to obtain proton den-
sity and T2* maps: 10 random initializations were performed and the
voxel- wise median value was used. The diffusion data were processed
in a similar way to a previous study19 to obtain maps of the appar-
ent diffusion coefficient (ADC) and the fractional anisotropy (FA).
Quantitative values were obtained as the mean over the entire pla-
cental parenchyma. Additional histogram- based evaluation was per-
formed for the T2* values resulting in skewness and kurtosis values.
2.4 | Ethical approval
The data used for this study were acquired as part of three ethi-
cally approved studies reviewed by the relevant ethical commit tees:
19- SS- 0032 (Inflammation study in pregnancy, South East Scotland,
approval received March 7, 2019), 19/LO/0852 (CARP study,
London— Dulwich Research Ethics Committee, approval received
July 24, 2019) and 14/LO/1169 (Placenta Imaging Project, Fulham
Research Ethics Committee, approval received September 23, 2016).
3 | RESULTS
In total, 12 women with PPROM were successfully scanned (only
the second scan from the one woman who underwent two scans
has been included in the analysis). Eight y- seven control pregnancies
were included for comparison. For the PPROM cohort, mean gesta-
tional age (GA) at MRI was 26+5 weeks (range 19– 33+ weeks), mean
GA at delivery 29+2 weeks (range 20+1– 3 3 +3 weeks) with median du-
ration from MRI to delivery 23+2 days (range 3– 106 days). For the
contro l co hor t, me dian GA was 29+3 weeks . The pregna nc y and bir th
outcomes for the PPROM cohort are given in Table 2.
Complete anatomical and relaxometry data were obtained and
processed in all cases. Diffusion data were obtained in all cases, but
judged of sufficient quality in only 10 cases. Histopatholog y results
are given in Table 3 for the PPROM cases, illustrating some degree
of mate rnal and/or fetal inflammatory response in all but one (corre-
sponding to P10, P11). No signs of villitis, intervillitis, infarction, ad-
ditional fibrin deposition, or accelerated maturation were obser ved
in any of the control or PPROM cases. From the control cohort, 26
women had histological assessment, of which eight showed no sign
of chor i oam n ion i tis an d 18 sh ow e d sig ns of ch ori o amn i oni t is at term .
Placental images from the 12 cases with PPROM, including the
10 scans with histopathological evidence of chorioamnionitis, are
displayed graphically in Figure 2, with the later scan used for the
TAB LE 2 Outcome for the PPROM cohort
ID
Time
ROM- MRI
GA MRI
(weeks)
GA delivery
(weeks)
Time MRI- delivery
(days) T2* Diff Gender
Birthweight
(centile)
1 (1) 226.14 2 8.14 14 xQ- Female 82.9
2 (2) 727 28.3 9 x x Male 79. 6
3 (4) 630.57 33 17 x x Female 34.6
4 (5) 225.86 29. 3 25 x x Female 88.6
5 (6) 429. 71 30.3 4x x Male 5.9
6 (9) 633 33.3 3 x Q- Male 83.8
7 (12) 626.29 28.14 13 x x Female 5 7. 7
8 (13) 229 31.56 11 x x Female 61 .6
9 (14) 3 30 30.3 3 x x Male 68.6
10 (15) 24 20.6 31.57 77 x x Female 37.4
11 (1502) 53 24.7 31.57 106 xQ- Female 3 7. 4
12 (225) 719.42 +(20 .14) +(5) x x + +
13 (291) 24 24.14 26. 57 16 x x MALE 76. 7
Note: ‘+’ signifies stillbir th before 23 weeks of gestation. Prolonged membrane rupture (ROM) times of more than 5 days are marked in yellow. Short
intervals bet ween MRI and delivery are marked in red (<5 days), yellow (5– 25 days)*. Data set s with low qualit y that had to be excluded are marked
with Q- .
Abbreviations: GA, gestational age; MRI, magnetic resonance imaging; ROM, rupture of membranes.

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woman who was scanned twice as outlined above. For each case,
coronal and sagittal anatomical images through the placental pa-
renchyma are given in the first row, together with a zoom into the
cervix, to visualize length and degree of dilation. In the second row,
T2*, ADC and FA maps are displayed for similar locations. The same
scales are used for each functional categor y for all placentae.
3.1 | Visual appearances
Anatomical changes were apparent in the sagittal displays for
PPROM cases P1 and P5 with large areas of hypointensit y close to
the chorionic plate (marked with green arrows), that were not seen in
control placentae. Smaller hyperintense areas were observable (pink
arrows) in most cases but these were not present in the control cases
of similar gestation.25
Control T2* maps25 show an increasingly lobular appearance
with more pronounced circular hyperintensive areas surrounded by
hypointense structures over gestation. These changes typically oc-
curred homogeneously over the entire placenta. However, the T2*
maps of the PPROM cases reveal pronounced, focal large areas of
low signal— as indicated with green arrows in PPROM placentae P1,
P2, P5, P6, P9, P12, and P13— which were not as visible in the ana-
tomical images from the majority of women. P10 and P11, from the
same woman, do not display these signs.
3.2 | Quantification
Figure 3 illustrates for the control women a decrease in mean T2*
over GA (controls slope −3.49, p < 0.005), decrease in ADC over GA
(Controls slope 0.55, p < 0.005) and an increase in FA (Controls slow
0.62, p < 0.005). Compared with these control values, the measure-
ments from the PPROM placentae show decreased mean T2* across
the GA range (PPROM cases slope −1.53, p = 0.295), with a wider
spread of values, although at a non- significant level. One notable
exception, case P8, is marked by the black arrow. In addition, the
ADC was not significantly reduced across GA from PPROM pla-
centae (PPROM cases slope 0.42, p = 0.04) and the FA values were
increased (PPROM cases slope 0.63, p = 0.005), compared with con-
trols. Analysis of the progression over GA was per formed to fit the
known dependency of these quantities with GA.
The evaluation of these quantitative measures against histo-
pathologically shown chorioamnionitis including the entire control
ID
Maternal inflammatory
indicators Fetal inflammatory indicators
P1 Severe acute
chorioamnionitis
Umbilic al cord vasculitis (vein)
P2 Acute chorioamnionitis Umbilic al vasculitis (3/3 vessels),
neutrophils extending into Whar ton‘s
jelly (funisitis), inflammation in the
chorionic plate, occlusion of large
central chorionic vessel, downstream
focus of ischemic villi
P3 Acute chorioamnionitis Acute chorionic vasculitis, acute umbilic al
cord vasculitis (1/3 vessels, acute
funisitis)
P5 Acute chorioamnionitis Funisitis and chorionic vasculitis, two
large non- occlusive thrombi in fetal
stem villi
P6 Acute chorioamnionitis Funisitis
P7 Acute chorioamnionitis Funisitis and vasculitis
P8 Acute chorioamnionitis Pan- vasculitis, chorionic plate is acutely
inflamed
P9 Acute chorioamnionitis Acute chorionic vasculitis, acute vasculitis
(3/3 vessels), acute funisitis
P10, 11 No chorioamnionitis No funisitis and no vasculitis, Occasional
intravillous hemorrhages
P4 No histology
P12 No histology
P13 No histology
Note: Colors emphasize normal finding (green), early stage of abnormalit y (orange), advanced, and
very advanced s tages (red and dar k red). There were no signs of infarction, increased perivillous
fibrin deposition, or evidence for decidual vasculopathy and all placentae showed normal
maturation.
TAB LE 3 Histopathological evaluation
for the participants

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HUTT ER ET al.
cohort (Figure 4) did not reveal any clear correlation. However, the
time between the MRI and the observed evidence for chorioamni-
onitis did vary largely, as is indicated by the transparency level in
Figure 4— hampering our ability to draw conclusions.
4 | DISCUSSION
This study demonstrates, as far as we are aware, the first explora-
tion of functional placental assessment in a cohort of women with
PPROM compared with control women who delivered at term with
uncomplicated pregnancies. We have demonstrated that multi-
modal functional MRI data can successfully be obtained from
women with PPROM. Trends for normal controls19 were reaffirmed:
ADC and mean T2* values decreasing and FA values increasing
linearly with gestation. There were both qualitative and quantitative
changes in PPROM cases, with an increase in FA values, no decrease
in ADC, and a trend towards a reduction in T2* values.
There are several recent studies using MRI to study PTB, but
these have focused on volumetric assessment of fetal organs. They
found a reduction in lung volume26 and changes in the size of the
thymus gland— known to play an integral role in the development of
the fetal immune system and suggested as a marker of the fetal in-
flammatory response.27 Previous efforts to assess the placenta spe-
cifically detected changes of a bank- like T2- weighted hypointense
signal and dif fusion- weighted hyperintense signal changes associ-
ated with a diagnosis of chorioamnionitis in three of six patients.28
This current study goes beyond anatomical assessment and includes
functional MRI properties of the placenta, which could complement
fetal findings.
FIGURE 2 Imaging results of all preterm prelabor rupture of membranes (PPROM) cases P1– P13. P10 was omitted and the second
scan of this woman, P11, was included. For each case, the anatomical images are displayed in the first row, coronal placental view, sagittal
placental view and sagitt al cervix view. The second row gives the functional T2* data in coronal and sagittal view matched to the anatomical
data. Pink arrows identify regions of hyperintense small dots. Green arrows identif y areas of reduced T2*. In the right column three
exemplar y controls are shown at similar gestational age

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The use of T2 and T2* relaxometry as a means of discrimi-
nating between acute and chronic phases of inflammation has
previously been proposed in other organs such as the heart and
the kidney13 and diffusion MRI has been used in the evaluation
of inflammator y conditions of the gastrointestinal tract such as
Crohn's disease.14 However, no studies to date have evaluated
whether these techniques can be used successfully to assess pla-
cental inflammation and hence may be indicative of chorioamni-
onitis in utero.
The quantitative values found in the control cohort are in ac-
cordance with literature values at 3T, showing decreasing T2* from
approximately 100 to 20 ms and ADC and FA values between 0.002
an d 0.0 03 mm2/ms and 0.3– 0.9 (arbitrary units) from 10 to 40 weeks,
respectively.1 7,1 9 Analysis of the PPROM cases revealed a number
of changes in the placental parenchyma both visually and numer-
ically reduced T2* values and markedly increased FA ( p = 0.005).
The observed heterogeneity in T2* values within the PPROM cohort
reflects the complicated and highly dynamic physiological changes
associated with ascending infection and the variability between time
of imaging and subsequent delivery.
The qu antit at iv e changes obs erv ed in the pl ac en tae of PP RO M
pregnancies demonstrate a similar ph enotype to women wit h pre-
eclampsia who present with a reduction in placental T2* and ADC
values and an increase in FA,19 although changes in PPROM are
not as marked, when compared with the control group, and ap-
pear to be more localized. This potentially points towards a less
extreme and more acute placental change in the PPROM cohort.
It should be noted that none of the women with PPROM, nor any
of the control cases, had hypertensive disorders of pregnancy or
other diagnoses typically associated with placental insufficiency.
The focus of this study is on PPROM pregnancies and associated
phenotypes; however, the study design does not allow us to dif-
ferentiate at this stage between placental insufficiency and in-
flammatory responses.
Increased FA values, evident in most PPROM cases, com-
bined with decreased ADC in three cases may be indicative of
microstructural changes within the placenta. Increased presence
of neutrophils in the corresponding tissue could decrease diffu-
sivity (reduced ADC value), and increased anisotropy (increased
FA value) could reflect localized infiltration in the chorion. The
FIGURE 3 Quantitative results from magnetic resonance imaging data in cohort s of control women and women with preterm prelabor
rupture of membranes (PPROM). T2* relaxometry and diffusion results of all c ases against gestational age (GA). The (A) mean T2*, (B)
apparent diffusivity coefficient (ADC) and (C) fractional anisotropy (FA) values are illustrated. Controls are marked with gray dots, PPROM
cases with colored squares. The colors indicate GA at birth and the size of the square indicates the time between scan and delivery, the
shorter the inter val the larger the square. The black arrow highlights subject P8
FIGURE 4 Quantitative results from magnetic resonance imaging data in cohort s of control women and women with preterm prelabor
rupture of membranes (PPROM). T2* relaxometry and diffusion results of all c ases against gestational age (GA). The (A) mean T2*, (B)
apparent diffusivity coefficient (ADC) and (C) fractional anisotropy (FA) values are illustrated. Controls are marked with dots, PPROM cases
with squares. The colors indicate information on histopatholog y. Red indicates the presence of chorioamnionitis, blue its absence and gray
signifies that no histopathological assessment was conducted. The transparency level indicates the time between scan and deliver y, the
shorter the inter val the less transparent the sign

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HUTT ER ET al.
observed reduced T2* could be linked to reduced transport of ox-
yge nated hemo gl obin as a down str ea m effect of the infl am matio n.
However, the cited changes in structure, the changed water con-
tent as well as any other changed tissue property might influence
the transverse relaxation rates.
The cases of PPROM with the longest period since ROM and the
shortest time inter val to delivery (cases P5, P6, and P9) displayed the
clearest phenotype, which is in line with the inflammation being the
most acute in these cases. Other cases such as P4, P12, P7, P10, and P11
displayed minimal changes compared with control women. The normal
histopathologic al evaluation in P10, P11 might indicate no sign of inflam-
mation which corresponds to this result. This observed variation on MRI
is likely to reflect several factors involved in PTB, such as inflammation,
cervical changes among other, and severity of chorioamnionitis, which
initiall y affect s the mate rn al compar tm ent before prog re ssing to the fetal
tissues, resulting in differing characteristics on placental histology.2 9 – 3 1
The maternal inflammatory response is characterized first by mi-
crobial invasion of the chorion, amnion, and chorionic plate before pro-
gression to epithelial necrosis of the amnion.23,29 Where this process is
localized to a specific area of the placenta (such as for case P2) mean
T2* is not as low as in cases where the invasion is more diffuse (cases P1
and P5 for example). In addition to the chorionic plate, more advanced
disease may also affe ct the amnion combi ned with vasculitis of th e cho -
rionic vessels. Further disease progression results in the fetal inflamma-
tory response, which is associated with poorer neonatal outcomes.32
This is characterized by leukocyte infiltration of the umbilical cord ves-
se l wa ll or Wh art on's jelly. Su ch change s ar e, however, hard er to id ent if y
from the MRI results bec ause of the small diameter of the vessels and
the variability in location. However, the most significant fetal compart-
ment infec tion is associated with the presence of thrombi within the
villous tree.32 This may be reflected by the substantially reduced T2*
areas: the distribution of these is in accordance with placental lobules
ref lec te d by in di vi du al villo us trees and the pr es ence of a throm bu s may
result in tissue with a reduction in oxygen content.
These findings may have clinical implications in the future to as-
sess the extent of chorioamnionitis and stratify individual patients'
risks accordingly. It would also be of interest to combine both fetal
and placental MRI findings to grade disease process and duration.
The lack of a reference st andard technique to assess for signs
of inflammation in vivo, specifically at the time of MRI, hinders
further evaluation. Although histopathological assessment of the
placenta after delivery facilitates a definitive diagnosis, it is under-
taken at a time- point remote from the MRI. In this study, the time
between delivery and MRI varied between 2 and 27 days for the
PPROM cases. Furthermore, the time between ROM and the scan
also varied bet ween 2 and 7 days, further limiting conclusions that
can be drawn. The targeted patient cohort, women with PPROM,
and the resulting unpredictable and short time window (delivery in
50% of cases within a week) and need for close clinical observation
during the scan render this study highly challenging; however, they
also make this data set unique. In future, expansion of the study will
allow grouping along similar timings and hence more insight into the
dynamic s of the observed challenges.
Given the course of the ascending infection traversing each layer
from decidua to chorion to amnion, a higher resolution and greater
focal evaluation would add specificity to the assessment of the tim-
ing of the infection and inflammatory response. Further advances in
MRI acquisition and reconstruction strategies would enable the use
of further high resolution three- dimensional reconstruction tech-
niques33 and so facilitate this in the future. Efforts to display the
placental tissues in an agreed coordinated system could further add
to the specificity of the loc alization of lesions.34, 35
To usefully translate these results, following a larger observa-
tion study, would be a randomized control trial to assess whether
altering the timing of delivery in PPROM in response to MRI bio-
markers of infection/inflammation could result in a reduction
in neonatal morbidity and mortality. Combined analysis with
biomarker- based serum scores might further enable the develop-
ment of individual risk scores.36,37 Phenotyping different presenta-
tion s in mo re de t ail tog et h er wi th histopa tho logic al as ses sme nt wi ll
allow additional insights into the cascade of events star ting from
the ascending infection through the layers of the placenta to wide-
spread fetal infection.
5 | CONCLUSION
Functional placental MRI reveals a range of placental changes, as-
sociated with inflammatory processes confirmed on subsequent
histolog y. It shows promise as a tool to noninvasively identify inflam-
mation in vivo, and could therefore assist in improving optimal timing
for interventions designed to prevent fetal injury, such as antenatal
corticosteroids and magnesium sulfate and the need for delivery
and/or in utero transfers where indicated.
CONFLICT OF INTEREST
AHS is the chief investigator on a number of trials funded by NIHR
and charity sources related to preterm birth prediction and pre-
vention. Clinical Innovations provided the ROM Plus® Rupture of
Membranes Tests for this study. Hologic Biomedical and Qiagen
have provided samples for these studies. Hologic have provided
funding (paid to the institution) to evaluate technical per formance of
their samples. There are no other conflicts of interest.
AUTHOR CONTRIBUTIONS
JH and LJ: data collection, writing, editing. AH: recruitment, data
collection, writing, editing. CAZ: data collection. JH, MA- A, SN and
AHS: data collection, editing. RMT and DG: editing. MAR and LS:
data collection, funding, editing.
ORCID
Jana Hutter https://orcid.org/0000-0003-3476-3500
Andrew H. Shennan https://orcid.org/0000-0001-5273-3132
Rachel M. Tribe https://orcid.org/0000-0003-3675-9978
Deena Gibbons https://orcid.org/0000-0002-7953-3576
Mary A. Rutherford https://orcid.org/0000-0003-3361-1337

2252
|
HU TTER E T al.
Lisa Sto ry https://orcid.org/0000-0001-9328-9592
REFERENCES
1. National Collaborating Centre for Women's and Children's Health
(UK). Preterm Labour and Birth. National Institute for Health and
Care Excellence (UK); 2015.
2. Nasef N, Shabaan AE, Schurr P, et al. Effect of clinic al and histo-
logical chorioamnionitis on the outcome of preterm infants. Am J
Perinatol. 2013;30:59- 68.
3. Mangham L J, Petrou S, Doyle LW, Draper ES , Marlow N. The cos t
of preterm birth throughout childhood in England and Wales.
Pediatrics. 2009;123:e312- e327.
4. Mercer BM. Preterm premature rupture of the membranes. Obstet
Gynecol. 20 03;101:178- 193.
5. Thomas W, Speer CP. Chorioamnionitis: important risk fac-
tor or innocent bystander for neonatal outcome? Neonatology.
2 0 1 1 ; 9 9 : 1 7 7 - 1 8 7 .
6. Morris JM, Roberts CL, Bowen JPJ, et al. Immediate delivery com-
pared with expectant management after preterm pre- labour rup-
ture of the membranes close to term (PPROMT trial): a randomised
controlled trial. Lancet. 2016;387:444- 452.
7. Peaceman AM, Lai Y, Rouse DJ, et al. Length of latency with preterm
premature rupture of membranes before 32 weeks’ ges tation. Am J
Perinatol. 2015;32:57- 62.
8. Thomson AJ. Royal College of Obstetricians and Gynaecologists.
Care of women presenting with suspected preterm prelabour
rupture of membr anes from 24+0 weeks of gestation. BJOG.
2019;126 :e152- e166 .
9. Blackwell SC, Berry SM. Role of amniocentesis for the diagnosis of
subclinical intra- amniotic infec tion in preterm premature rupture of
the membranes. Curr Opin O bstet Gynecol. 1999;11:541- 5477.
10. Ramsey PS , Lieman JM, Brumfield CG, et al. Chorioamnionitis
increases neonatal morbidity in pregnancies complicated by
preterm premature rupture of membranes. Am J Obstet Gynecol.
20 05;19 2:1162- 1166.
11. Merenstein GB, Weisman LE. Premature rupture of the mem-
branes: neonatal consequences. Semin Perinatol. 1996;20:375- 380.
12. Kamdar S, Hutchinson R , Laing A, et al. Perinatal inflammation in-
fluences but does not arrest rapid immune development in preterm
babies. Nat Commun. 2020;11:1284.
13. Gee MS, Harisinghani MG. MRI in patient s wit h inflammatory
bowel disease. J Magn Reson Imaging. 2011;33:527- 534.
14. Pouillon L, Laurent V, Pouillon M, et al. Diffusion- weighted MRI,
Lancet . Gastroenterol Hepatol. 2018;3:433- 443.
15. Bohnen S, Radunski UK , Lund GK, et al. Tissue characterization by
T1 and T2 mapping cardiovascular magnetic resonance imaging to
monitor myocardial inflammation in healing myocarditis. Eur Heart J
Cardiovasc Imaging. 2017;18:74 4- 751.
16. Sørensen A, Peters D, Fründ E, Lingman G, Christiansen O,
Uldbjerg N. Changes in human placental oxygenation during ma-
ternal hyperoxia estimated by blood oxygen level- dependent mag-
netic resonance imaging (BOLD MRI). Ultrasound O bstet Gynecol.
2013;42:310- 314.
17. Ho AEP, Hutter J, Jackson LH, et al. T2* placental magnetic reso-
nance imaging in preterm preeclampsia. An Obser vational Cohor t
Stu dy. Hypertension. 2020;75:1523- 1531.
18. Sinding M, Peters DA, Frøkjær JB, et al. Placental magnetic res-
onance imaging T2* measurements in normal pregnancies and in
those complicated by fetal grow th restric tion. Ultrasound Obstet
Gynecol. 2016;47:748- 754.
19. Hutter J, Slator PJ, Jackson L, et al. Multi- modalfunctional MRI
to explore placental function over gestation. Magn Reson Med.
2019;81:1191- 1204.
20. Dellschaft NS, Hutchinson G, Shah S, et al. The haemodynamics of
the human placent a in utero. PLoS Biol. 2020;18:e3000676.
21. Melbourne A, Aughwane R, Sokolska M, et al. Separating fetal and
maternal placenta circulations using multiparametric MRI. Magn
Reson Med. 2019;81:350- 361.
22. Slator PJ, Hutter J, Palombo M. Combined diffusion- relaxometr y
MRI to identify dysfunction in the human placenta. Magn Reson
Med. 2019;82:95- 106.
23. Redline RW. Inflammatory responses in the placenta and umbilical
cord. Semin Fetal Neonatal Med. 20 06;11:296- 301.
24. Gaspar AS, Nunes RG, Ferrazzi G, et al. Optimizing maternal fat
suppression with constrained image- based shimming in fetal MR.
Magn Reson Med. 2019;81:477- 485.
25. Hutter J, Jackson L, Ho A, et al. T2* relaxometr y to characterize nor-
mal placental development over gestation in- vivo at 3T [version 1;
peer review: 1 approved, 1 approved with reservations]. Wellcome
Open Res. 2019;4:166. doi: 10.12688/ wellc omeop enres.15451.1
26. Story L, Zhang T, Steinweg JK, et al. Foetal lung volumes in preg-
nant women who deliver very preterm: a pilot study. Pediatr Res.
2020;87:1066- 1071.
27. Story L, Zhang T, Uus A, et al. Antenatal thymus volumes in fetuses
that deliver <32 weeks gestation: an MRI pilot s tudy. Acta Obstet
Gynecol Scand. 2021;100 :104 0- 1050.
28. Linduska N, Dekan S, Messer schmidt A, et al. Placental pathol-
ogies in fetal MRI with pathohistological correlation. Placenta.
200 9;30:555- 559.
29. Cappelletti M, Presicce P, Kallapur SG. Immunobiology of acute
chorioamnionitis. Front Immunol. 2020;11:649.
30. Arias F, Victoria A, Cho K, K raus F. Placental histology and clini-
cal characteristics of patients with preterm premature rupture of
membranes. Obstet Gynecol. 1997;89:265- 271.
31. Morgan TK. Role of the placenta in preterm birth: a review. Am J
Perinatol. 2016;33:258- 266.
32. Kim CJ, Romero R , Chaemsaithong P, Kim JS. Chronic inflammation
of the placenta: definition, classification, pathogenesis, and clinical
significance. Am J Obstet Gynecol. 2015;213:S53- S69.
33. Uus A, Steinweg JK, Ho A, et al. Deformable slice- to- volume reg-
istration for reconstruction of quantitative T2* placental and
fetal MRI. In: Hu Y, et al. (Eds) Medical Ultrasoun d, and Preterm,
Perinatal and Paediatric Image Analysis. 2020, ASMUS 2020, PI PPI
2020. Lecture Notes in Computer Science, Vol. 12437. Springer.
1 0 . 1 0 0 7 / 9 7 8 - 3 - 0 3 0 - 6 0 3 3 4 - 2 _ 2 2
34. Abulnaga SM, Turk EA, Bessmeltsev M, Grant PE, Solomon J,
Golland P. Placental flattening via volumetric parameterization.
Med Image Comput Com put Assist Interv. 2019;11767:39- 47.
35. Miao G , Mistelbauer A, Karimov A, et al. Placenta maps: in utero
placent al health assessment of the human fetus. IEEE Trans Vis
Comput Graph. 2017;23:1612- 1623.
36. van der Krogt L, Ridout AE, Seed PT, Shennan AH. Placental inflam-
mation and its relationship to cervicovaginal fetal fibronectin in
preterm birth. Eur J Obstet Gynecol Reprod Biol. 2017; 214:173 - 177.
37. Korzeniewski SJ, Romero R, Chaiworapongsa T, et al. Maternal
plasma angiogenic index- 1 (placental growth factor/soluble vas-
cular endothelial growth fac tor receptor- 1) is a biomarker for the
burden of placental lesions consistent with uteroplacental under-
perfusion: a longitudinal case- cohort study. Am J Obstet Gynecol.
2016;214(5):629.e1- 629.e17.
How to cite this article: Hutter J, Jackson L, Ho A, et al. The use
of functional placental magnetic resonance imaging for
assessment of the placenta after prolonged preterm rupture of
the membranes in vivo: A pilot study. Acta Obstet Gynecol Scand.
2021;100:2244– 2252. htt ps://doi.org/10.1111/aogs.14267