Placental diffusion etimated by MRI in relation to birth weight difference in dichorionic twin pregnancy Ditte Nymark Hansen Kandidatspeciale, efterår 2015
Medicin, Aalborg Universitet
Placental diffusion estimated by MRI in relation to
birth weight difference in dichorionic twin pregnancy
Kandidatspeciale, Medicin Aalborg Universitet
Ditte Nymark Hansen Lægestuderende, 11. semester
Vejledere
Anne Sørensen, MD, PhD1, Marianne Sinding, MD1, Charlotte Overgaard, RM Msc, PhD2 og David A Peters, MSc, PhD3
1 Gynækologisk-Obstetrisk afdeling, Aalborg Universitetshospital, Aalborg, Danmark
2 Institut for Medicin og Sundhedsteknologi, Aalborg Universitet, Danmark
3 Indkøb og Medicoteknik, Region Midt, Aarhus, Danmark
Antal ord: 2880 ord (excl. dansk resumé: 917 ord og abstract: 367 ord)
Antal sider: 52 sider
Antal bilag: 4 (31 sider)
Afleveringsdato: 21. december 2015
Rapportens indhold er frit tilgængeligt, men offentliggørelse må kun ske efter aftale med forfatteren og med kildehenvisning.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 2 af 52
Indhold
Dansk resumé .................................................................................................................................................... 3
Læsevejledning .................................................................................................................................................. 7
Problembeskrivelse ........................................................................................................................................ 7
Etiske overvejelser ......................................................................................................................................... 7
Metode ........................................................................................................................................................... 8
Litteratur ........................................................................................................................................................ 9
Publikationsstrategi ....................................................................................................................................... 9
Article manuscript ........................................................................................................................................... 10
Abstract ....................................................................................................................................................... 10
Introduction ................................................................................................................................................. 11
Methods ....................................................................................................................................................... 13
Results ......................................................................................................................................................... 15
Discussion.................................................................................................................................................... 16
Conclusion ................................................................................................................................................... 19
Litteratur .......................................................................................................................................................... 19
Bilag ................................................................................................................................................................ 22
1. EpiData – Indtastningsark for “Placenta-databasen” ........................................................................... 22
2. SPSS syntax ......................................................................................................................................... 27
3. Litteratursøgning: Twin discordance ................................................................................................... 37
A. Søgeprotokol .................................................................................................................................... 37
B. Flowdiagram for søgning................................................................................................................. 39
C. Review-tabel .................................................................................................................................... 40
4. Litteratursøgning: Diffusion-Weighted Imaging ................................................................................. 47
A. Søgeprotokol .................................................................................................................................... 47
B. Flowdiagram for søgning................................................................................................................. 50
C. Review-tabel .................................................................................................................................... 51
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 3 af 52
Dansk resumé Intro
Antallet af tvillingegraviditeter er steget det sidste årti grundet øget maternal alder samt øget brug af
assisteret reproduktion. Tvillingegraviditeter er høj-risiko-graviditeter i forhold til negative
perinatale udfald, og ved vægtdiskordans hos tvillingeparret øges denne risiko yderligere. Det er
derfor væsentligt, at denne undergruppe af meget høj-risiko graviditeter opdages. Forudsigelse af
forskelle i fødselsvægt mellem de to børn i et tvillingepar (inter-twin) er præsenteret i litteraturen
med adskillige parametre, oftest med lav specificitet og sensitivitet. Føtale markører, som forskel i
isse-hale-længde (crown-rump length, CRL), abdominal omfang (AC) og estimeret føtal vægt
(EFW) er associeret med, men dårlige prædiktorer af, inter-twin forskel i fødselsvægt. Derfor er det
nødvendigt med nye markører til at forudsige inter-twin forskel i fødselsvægt.
Nylige studier antyder, at den placentære diffusion er nedsat i væksthæmmede singleton
graviditeter. Diffusion undersøges med Diffusion-Weighted (DWI) Magnetic Resonance Imaging,
der registrerer Brownske bevægelser af vandmolekyler, og diffusionskoefficienten (apparent
diffusion coefficient, ADC) er et kvantitativt mål for diffusionen i det undersøgte organ. ADC
beregnes ud fra signalintensiteten ved flere b-værdier (s/mm2). Ekstravaskulære bevægelser af
vandmolekyler (eks. diffusion) registreres ved højere b-værdier, mens intravaskulære bevægelser af
vandmolekyler (eks. perfusion) registreres ved lavere b-værdier. Lavere ADC værdier kan være
associeret med nekrose og infarkter, som er tæt associeret med placentainsufficiens, hvilket er én af
årsagerne til væksthæmning hos fostre. Hvis årsagen til vægtforskel hos tvillinger er væktshæmning
hos det ene af fostrene, kan placental diffusion være en potentiel markør for vægtforskel i
tvillingegraviditeter.
Målet med dette studie er at undersøge sammenhængen mellem forskellen i ADC-værdi i
tvillingeparrets placentae, estimeret med DWI MRI, og inter-twin forskellen i fødselsvægt.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 4 af 52
Metode
Videnskabsetisk Komité har godkendt studiet, og dataindsamling til specialet er anmeldt til
Datatilsynet.
25 gravide kvinder med dikoriske tvillinger blev inkluderet i studiet. 1 kvinde blev ekskluderet pga.
kontraktioner i uterus under DWI sekvensen, og 8 kvinder havde ikke født ved deadline for
rapporten. 16 MR-skanninger af dikoriske tvillingepar indgår derfor i databehandlingen i dette
studie.
MR-skanningerne blev gennemført i GE Discovery MR450 1.5 Tesla MRI System (GE Healthcare,
Milwaukee, USA). Anatomiske skanninger i frontal- og horisontalplan blev gennemført først for at
planlægge DWI sekvensen således, at begge placentae gennemskæres i tværsnit for at få både
maternel og føtal side med. DWI sekvensen gennemføres med 10 b-værdier (0-1000 s/mm2).
Én Region of Interest (ROI) indtegnes, så den dækker hele tværsnittet af hver placenta i MAT-LAB
baseret software lavet ”in-house”. Denne software beregner ADC-værdierne ved en lineær
tilpasning til gennemsnittet af signalintensiteten i de fem ROIs ved de tre højeste b-værdier (200-
1000 s/mm2).
Patientdata trækkes både ud fra den elektroniske patientjournal og ultralyds-journalen og indtastes i
EpiData Entry Client v. 2.0.5.17 – en specialiseret data-software for at minimere fejlindtastning.
Inter-twin forskelle i ADC-værdier og fødselsvægt (%) beregnes med udgangspunkt i fødselsvægt.
Inter-twin forskel i ADC-værdier beregnes ved (ADC-værdi_stor tvilling – ADC-værdi_lille
tvilling) / højeste ADC-værdi * 100 %. Inter-twin forskel i fødselsvægt beregnes ved
(fødselsvægt_stor tvilling – fødselsvægt_lille tvilling) / højeste fødselsvægt * 100 %. Diskordans
mellem tvillingerne defineres som inter-twin forskel i fødselsvægt >20 %.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 5 af 52
Parret t-test undersøger om inter-twin forskellen i ADC-værdi er signifikant. Lineær
regressionsanalyse og Pearsons correlation tester sammenhængen mellem inter-twin forskel i ADC-
værdi og inter-twin forskel i fødselsvægt. Alle dataanalyser blev gennemført i statistik-softwaren,
IBM SPSS Statistics version 22.0 (SPSS Inc., Chicago, IL, USA). Statistisk signifikans ved p <
0,05.
Resultater
Den gennemsnitlige inter-twin forskel i placental ADC-værdi var -0.03±9.45 % (mean±SD) for de
16 tvillingepar. Denne forskel var ikke statistisk signifikant (p-værdi = 0,989). Som følge heraf,
kunne der ved lineær regressionsanalyse og Pearson correlation ikke demonstreres en sammenhæng
mellem inter-twin forskelle i placental ADC-værdi og inter-twin forskelle i fødselsvægt (p-værdi =
0,872 og Pearson correlation 0,044, p-værdi=0,872).
Studiepopulationen indeholdt ét tvillingepar med diskordant fødselsvægt (inter-twin forskel i
fødselsvægt = 29,84 %). Inter-twin forskellen i ADC-værdierne for dette tvillingepar var -2,96 %
(1,64 (stor tvilling) vs. 1,69 mm2/s (lille tvilling).
Diskussion
Dette er, så vidt vi ved, det første studie, der undersøger den placentære diffusion i
tvillingegraviditeter.
Styrkerne ved studiet er, at ADC-værdien beregnes baseret udelukkende på højere b-værdier,
hvilket dermed udtrykker diffusionen alene i modsætning til tidligere studier, hvor perfusionen også
indblandes, samt at inter-twin forskellen i ADC-værdi beregnes med øje for hvilken ADC-værdi,
der hører til hvilken tvilling, hvilket betyder, at en evt. sammenhæng mellem diffusion og
fostervægt findes.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 6 af 52
Begrænsningerne ved dette studie er den meget lille studiepopulation (16 tvillingepar) og stor
variation i intervallet mellem MR-skanningen og fødsel (1,7 til 16,4 uger). Den gennemsnitlige
inter-twin forskel i ADC-værdi var blot -0,03 %, og vi tror derfor ikke at en større studiepopulation
ville ændre konklusionen. Der ses ingen sammenhæng mellem intervallet mellem skanning og
fødsel og inter-twin forskel i ADC-værdi. Dette indikerer at konklusionen ikke ville ændres selvom
dette tidsinterval blev reduceret.
Det er stadig uklart, hvad ADC-værdien i placenta præcist er et udtryk for, men med udgangspunkt i
brugen af ADC-værdi for andre organer, giver det anledning til nogle teorier. Placenta er et
heterogent organ med både væske-holdige områder, som det intervilløse rum, hvor
vandmolekylerne kan bevæge sig relativt frit (høj ADC), men placenta indeholder også mere
cellerige områder, hvor vandmolekylernes bevægelser er mere begrænsede (reduceret ADC).
Forkalkninger, der er associeret med infarkter i placenta, kan også reducere ADC-værdien.
Konklusion
Der er brug for en god prædiktor for vægtdiskordans hos tvillinger. Men ifølge vores data, er
placental ADC-værdi baseret udelukkende på diffusion (højere b-værdier) ikke en god markør for
inter-twin forskel i fødselsvægt.
Fremtidige MR-studier med placenta bør undersøge placentale ADC-værdier med lavere b-værdier
for at isolere perfusion, som en potentiel markør for at forudsige vægtdiskordans i
tvillingegraviditeter.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 7 af 52
Læsevejledning
Dette kandidatspeciale er en del af et igangværende Ph.d.-studie om MR-skanning af placenta i
”Placenta-gruppen” på Gynækologisk og Obstetrisk afdeling, Aalborg Universitetshospital.
Placenta-gruppen er en veletableret forskningsgruppe, der mødes ugentligt med formålet at lære nyt
indenfor forskningsmetode og udveksle erfaringer/resultater.
Problembeskrivelse I den kliniske dagligdag på en Obstetrisk afdeling er der ingen metoder til direkte at måle placentas
funktion. Ultralyd har en central plads i monitoreringen af den gravide, men ultralyd gør det kun
muligt at monitorere fostrets vækst og cirkulation, som begge dele er indirekte estimater af
placentafunktionen. Funktionelle MR-sekvenser gør det muligt at måle placentafunktionen direkte
og non-invasivt. I klinisk praksis ville det betyde, at placentaproblemer opdages, før fosteret
(outcome) påvirkes.
I dette speciale undersøges den placentære diffusion i tvillingegraviditeter. Specialet blev
gennemført fra 1. september til 10. december 2015. 25 kvinder med bekræftet dikorisk gemelli-
graviditet er inkluderet i studiet og MR-skannet med DWI protokol. 8 kvinder havde ikke født inden
deadline for denne rapport, og derfor indgår 17 gravide i selve artikelmanuskriptet, som følger
herunder.
Etiske overvejelser Videnskabsetisk Komité er ansøgt til hele MR-studiet, som også omfatter diffusionsskanningerne i
specialet (Journalnummer M-20090006 and N-20090052).
Den primære etiske overvejelse i studiet omhandler MR-skanning under graviditet. I 1. trimester
anbefales det kun at gennemføre MR-skanning på maternel indikation.1 Der er derimod ingen
sådanne anbefalinger ifht. 2. og 3. trimester. Der er desuden ikke brugt kontrast-stof under
skanningerne – brug af dette anbefales kun når risikoen ved at overse diagnose overstiger risikoen
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 8 af 52
ved brug af kontrast-stof under graviditet. Den maternelle risiko i forbindelse med MR-skanning er
som for ikke-gravide, dog kan længerevarende position fladt på ryggen resultere i vena cava
inferior-syndrom for gravide. Af denne grund lægges de gravide en smule skråt, med støtte under
ryggen under skanningen. De føtale risici indebærer varme fra det magnetiske felt under
skanningen. Ved 1.5 Tesla øges temperaturen for mor og foster ikke mere end anset for sikkert.
Lyden, der dannes under MR-skanning, er under undersøgelse, men der er ingen nuværende
resultater, der viser skadelig effekt af prænatal MR-skanning.2 Der er endnu ikke undersøgt
langtidskonsekvenser af MR-skanning over 3.0 Tesla. Derfor anbefales det ikke at overstige dette
ved prænatale skanninger.1 I dette studie benyttes 1.5 Tesla MRI system.
Kvinderne underskriver informeret samtykke. Her kan de afkrydse hvorvidt de ønsker at få
information om eventuelle fund og resultater i studiet. På denne måde sikres det, at deltagelse i
studie ikke medfører information, som kvinderne gerne ville være foruden.
Dataindsamling til specialet er anmeldt til Datatilsynet som en del af paraplyanmeldelsen for
Region Nordjylland – Journalnr.: 2008-58-0028, d. 14. september 2015.
Metode Softwaren ’EpiData’ er brugt til oprettelse af ”Placenta-databasen”. Opsætningen og
programmeringen af denne er foretaget i samarbejde med en anden kandidatspecialestuderende på
afdelingen, mens hele placenta-gruppen sammen er blevet enige om hvilke variable, der skal indgå i
Placenta-databasen. I databasen indtastes samtlige data for hver af de valgte variable for patienter,
der allerede indgår i de nuværende studier i Placenta-gruppen, og databasen kan udvides hver gang,
der inkluderes nye patienter. På denne måde kan fremtidige studier baseres på udtræk af data herfra.
Dataindtastning i EpiData minimerer risikoen for fejlindtastninger, da denne software samler
information om hver patient på egen indtastningsside. Felterne er desuden specificeret til svartypen.
Der er foretaget dobbeltindtastning af samtlige data og ved uoverensstemmelser blev der foretaget
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 9 af 52
kontrolopslag i originale journalnotater for at finde rette information. Dette for at minimere risikoen
for, at databehandlingen foregår med forkerte data. Udskrift af indstillinger og opsætning af
indtastningsark er vedlagt (Appendix, 1. EpiData – Indtastningsark for ”Placenta-databasen”).
Den statistiske analyse er gennemført ved brug af ”Syntax-fil”. Fordelen ved brug af syntax-fil er
dokumentation og gennemsigtighed af databehandlingen, men også at den sikrer systematik i
databehandlingen. Syntax-filen gør det også muligt at gentage eller efterprøve databehandlingen på
et senere tidspunkt. Syntax-udskrift er vedlagt (Appendix, 2. SPSS syntax).
Litteratur Systematisk litteratursøgning blev gennemført i starten af studieperioden (senest gennemført d. 26.
november 2015) for at sikre overblik over samt indsigt i emnet. Søgeprotokol, flowdiagram baseret
på PRISMA Statement 3 med udvælgelsen af litteratur fra søgningen og review-tabel over den
udvalgte litteratur er vedlagt (Appendix, 3. Litteratursøgning: Twin discordance og 4.
Litteratursøgning: Diffusion-Weighted Imaging)
Publikationsstrategi Prenatal Diagnosis har til formål at udgive resultater fra original forskning om blandt andet føtal og
placental fysiologi og patologi. Derfor er dette tidsskrift valgt, som mål for udgivelse af
nedenstående artikel. Artiklen er forsøgt klargjort så vidt muligt til indsendelse i henhold til
tidsskriftets ”Author Guidelines”4. Abstractet er dog tilpasset rapportens formalia (max. 400 ord) og
ikke tidsskriftets formalia (max. 200 ord). Derudover er figurer og tabellen indsat i teksten i
modsætning til ved indsendelse, hvor de sættes sidst, som tilpasning til rapport-format og for det
færdige udtryk. Derfor er der bl.a. heller ikke indsat linjenumre i det følgende artikelmanuskript,
som der ellers skal være ved indsendelse. Artikelmanuskriptet overholder desuden tidsskriftet krav
om max. 3500 ord og føler deres retningslinjer om citationsformat (Vancouver med hævede tal).
Specialets videnskabelige bidrag følger herunder i form af et artikelmanuskript.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 10 af 52
Article manuscript
Placental diffusion estimated by MRI in relation to birth weight difference in dichorionic twin pregnancy
Abstract
Objective
The prediction of inter-twin birth weight discordance by different markers is presented in the
literature with very low specificity and sensitivity. Fetal markers such as discordance in crown
rump length, abdominal circumference and estimated fetal weight (EFW) are associated with, but
poor predictors of, birth weight discordance. Therefore, new placental markers to predict inter-twin
birth weight discordance are highly needed.
Recently, it has been suggested that placental diffusion is reduced in FGR singleton pregnancies,
which makes it a potential marker for weight discordance in twin pregnancies.
The aim of this study was to investigate the association between inter-twin placental apparent
diffusion coefficient (ADC) differences, estimated by diffusion weighted imaging (DWI), and inter-
twin birth weight differences.
Methods
We retrospectively evaluated 1.5T placental magnetic resonance imaging (MRI) using the DWI
sequence (10 b-values in range from 0-1000 sec/mm2) from 17 dichorionic twin pregnancies
(gestational age 20+4 to 35+4 weeks). One pregnancy was excluded from the analysis because of
contractions during the DWI sequence. Regions of interest were drawn in five slices in each
placenta. ADC values (mean of 5 slices) were calculated as a linear regression analysis in each
placenta, based on the signal intensity in the three highest b-values (200-1000 sec/mm2) of the MRI.
Inter-twin placental ADC differences were calculated as the placental ADC value of the smaller
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 11 af 52
twin subtracted from the placental ADC value of the larger twin, expressed as a percentage of the
larger ADC value. Inter-twin birth weight differences were calculated as the birth weight of the
smaller twin subtracted from the birth weight of the larger twin, expressed as a percentage of the
larger birth weight.
The hypothesis that placental ADC was lower in the smaller twin when compared to the larger co-
twin was tested using a paired t-test. The association between inter-twin placental ADC differences
and the inter-twin birth weight differences was investigated using linear regression.
Results
The mean inter-twin placental ADC difference was -0.03±9.45 % (mean±SD). This difference was
not significant, when tested using a paired t-test, p-value = 0.989. Consequently, no association
could be demonstrated between the inter-twin placental ADC difference and the inter-twin birth
weight difference.
Conclusion
Placental ADC is not a good marker of inter-twin birth weight difference.
Introduction
The incidence of twin pregnancies has increased over the last decades.5 This is due to increasing
maternal age and increased use of assisted reproduction. Twin pregnancies are associated with
increased risk of adverse perinatal outcomes 6–10 and inter-twin birth weight discordance is
associated with even worse perinatal outcomes.10 Therefore prediction of inter-twin weight
discordance is important to identify the subgroup of very high-risk pregnancies. Several fetal
variables such as ultrasound estimated fetal weight11–20, crown-rump length21,22, abdominal
circumference16,23 and fetal head and trunk volume 24 are associated with birth weight discordance
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 12 af 52
in twin pregnancies. However, only a few of these studies predict inter-twin birth weight
discordance, when estimated more than 3 weeks prior to birth21,22,24.
Direct placental markers such as placental T2*25 and placental perfusion26,27 have previously been
investigated. However, none of these markers have been correlated to birth weight discordance.
Direct placental markers are interesting, since a very common cause for fetal growth retardation is
placental insufficiency. Only a few previous studies have investigate placental markers of birth
weight discordance28,29. Geipel et.al.28 found low sensitivity for abnormal mean uterine pulsatility
index to predict birth weight discordance, and Belogolovkin et.al.29 failed to demonstrate any
correlation between placental location and birth weight discordance.
Diffusion-weighted (DWI) magnetic resonance imaging is traditionally used as a diagnostic tool in
neurology and neurosurgery. The DWI sequence registers the random movements of water
molecules (Brownian motions) and the apparent diffusion coefficient (ADC) is calculated as a
quantitative non-directional measurement of the diffusion in the tissue of interest. In the brain,
ischemia causes cellular edema and therefore reduced movements of the water molecules, causing
the cerebral ADC to decrease. ADC calculation is based on signal intensity at different b-values
(sec/mm2). ADC values calculated with bi-exponential fit with both lower and higher b-values
consist of two compartments. Movement of intravascular water molecules (like perfusion) are
represented at the first compartment which is predominant at lower b-values, while movement of
extravascular water molecules (like diffusion) are represented at the second compartment which is
predominant at higher b-values30,31. Bonel et.al.32 and Chantraine et.al.33 found placental ADC to be
reduced in fetuses with intra uterine growth restriction (IUGR). This finding indicates that placental
ADC has the potential to predict growth restriction.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 13 af 52
The aim of this study was to investigate the association of inter-twin placental ADC differences,
estimated by diffusion weighted imaging (DWI), and inter-twin birth weight differences. To our
knowledge, this is the first study to investigate placental diffusion in twin pregnancies.
Methods
The study is approved by the Regional Committees on Biomedical Research Ethics (Journal number
M-20090006 and N-20090052). Oral and written informed consents were obtained from all
participating women.
17 dichorionic twin pregnancies confirmed at nuchal translucency scan (11+1 to 13+6 weeks) at the
ultrasound department at Aalborg University Hospital were included in this study and scanned with
DWI sequence. Gestational age was determined at this ultrasound scan based on the crown-rump
length of the larger twin. One woman was excluded because of contractions during the DWI-
sequence. A total of 16 dichorionic twin pairs were used for analysis in this study.
The MR imaging was performed in a GE Discovery MR450 1.5 Tesla MRI System (GE Healthcare,
Milwaukee, USA). Localizer images were acquired in coronal and transverse planes to plan the
DWI sequence to get a cross section of both of the placentas. DWI sequence was performed during
free maternal breathing with a body array coil using 10 b-values, range from 0 to 1000 sec/mm2.
Acquisition time of the complete DWI sequence is 4.48 minutes. No sedation or contrast was
administered. Supine position, left lateral tilt and “feet first” modality was used to minimize
discomfort from compression of the inferior vena cava and the risk of claustrophobia of the
pregnant women.
One Region of Interest (ROI) covering each of the placentas in a cross section (Figure 1) was drawn
in in-house developed software written in MAT-LAB, RoiTools version 3.71 (The MathWorks Inc.,
Natick, MA). ROIs were drawn in 5 different, evenly distributed slices per placenta. The drawer
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 14 af 52
was blinded to patient information when
drawing the ROIs. The MAT-LAB
software calculated the ADC values as a
linear regression analysis based on the
signal intensity in the three highest b-
values (200-1000 sec/mm2) as a mean of
the five slices of each placenta (Figure 2).
Data from delivery ward and the obstetric
ultrasounds were conducted from the
electronic patient system. All data were
entered in specialized software, EpiData
Entry Client v. 2.0.5.17 based on an
entry sheet made in specialized software,
EpiData Manager v. 2.0.7.53 (EpiData
Association, Odense, Denmark).
Inter-twin placental ADC differences were
calculated as the placental ADC value of
the smaller twin subtracted from the
placental ADC value of the larger twin, expressed as a percentage of the larger ADC value.
Inter-twin differences (%) in birth weight were calculated as birth weight of the smaller twin
subtracted from the birth weight of the larger twin, expressed as a percentage of the largest birth
weight. Twin discordance is defined as inter-twin birth weight difference > 20 %.
Figure 2: Screen print from the MAT LAB software „ROItools‟. The best fitted line is calculating the placental ADC value for one placenta based on signal intensity in the three highest b-values (200-1000 sec/mm2) as a mean of 5 slices. a.u. = arbitrary unit.
Figure 1: Diffusion-Weighted MR image of the uterus in longitudinal section with drawing of two Regions of Interests. Placenta for twin 1 marked by dark blue (in the fundal part of uterus), placenta for twin 2 marked by lighter blue (on the anterior uterine wall).
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 15 af 52
Normal distribution of the data for the variables; inter-twin difference in placental ADC, inter-twin
difference in birth weight and time between MRI and birth was tested using histograms, Q-Q-plots
and the Shapiro-Wilk Test prior to statistical analyses. The inter-twin placental ADC difference was
tested using a Paired t-test. The association between inter-twin placental ADC differences (%) and
inter-twin birth weight differences (%) was tested using linear regression analysis and Pearson’s
correlation. All data analyses were made in statistical software, IBM SPSS Statistics version 22.0
(SPSS Inc., Chicago, IL, USA). Statistical significance was set at p<0.05.
Results
The data and calculations of the study population are summarized in table 1.
Table 1: Data and calculations for the study population
Twin pair
GA at MRI
(weeks)
ADC value larger twin (x10-3
mm2/sec)
ADC value
smaller twin (x10-3
mm2/sec)
Inter-twin ADC
difference (%)
Time between
MRI and
birth (weeks)
GA at birth
(weeks)
Birth weight larger twin
(gram)
Birth weight smaller
twin (gram)
Inter-twin birth
weight difference
(%)
1 32.4 1.41 1.49 -5.37 4.9 37.3 2800 2770 1.07 2 35.6 1.51 1.39 7.95 1.7 37.3 3000 2660 11.33 3 21.0 1.58 1.54 2.53 16.0 37.0 2880 2750 4.51 4 24.7 1.63 1.65 -1.21 11.3 36.0 2570 2235 13.04 5 21.6 1.84 1.69 8.15 12.4 34.0 2700 2490 7.78 6 20.6 1.64 1.69 -2.96 11.7 32.3 1910 1340 29.84* 7 24.6 1.67 1.54 7.78 13.5 38.1 2750 2570 6.55 8 24.3 1.56 1.73 -9.83 13.6 37.9 2890 2680 7.27 9 26.9 1.61 1.46 9.32 4.2 31.1 1228 1223 0.41
10 23.7 1.72 1.43 16.86 14.4 38.1 3370 3100 8.01 11 23.4 1.45 1.65 -12.12 11.0 34.4 2040 1945 4.66 12 24.7 1.32 1.38 -4.35 13.4 38.1 2940 2810 4.42 13 21.3 1.44 1.69 -14.79 16.4 37.7 2670 2590 3.00 14 21.1 1.40 1.43 -2.10 15.5 36.6 2750 2735 0.55 15 25.6 1.65 1.47 10.91 11.4 37.0 2430 2190 9.88 16 32.7 1.49 1.68 -11.31 5.4 38.1 3100 2770 10.65
Mean±SD -0.03±9.45
Median (range) 12.0
(1.7-16.4) 6.91 (0.41-29.84)
GA = gestational age (calculated by dividing number of days beyond full weeks with 7, e.g. 32+4 = 32.6 weeks). Inter-twin difference = (larger twin value - smaller twin value) / larger value x 100 %. *discordant twin pair (> 20 % birth weight difference).
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 16 af 52
For the 16 twin pairs, the median inter-twin birth weight difference was 6.91 % (0.41-29.84 %)
(median (range)). The mean inter-twin placental ADC difference was -0.03±9.45 % (mean±SD)
(Table 1). The inter-twin placental ADC difference was not statistically significant (p-value =
0.989).
There was only one discordant twin pair
(inter-twin birth weight difference (%) >
20%) in this study, 6.3% (n=1). In this
particular twin pair the inter-twin placental
ADC differences (%) was -2.96 % (1.64 and
1.69 x 10-3 mm2/sec, Table 1).
A linear regression analysis (Figure 3)
confirms that no association could be
demonstrated between inter-twin difference in
placental ADC and inter-twin difference in birth
weight (p-value = 0.872). Pearson correlation 0.044 (p-value=0.872).
Discussion
The inter-twin placental ADC difference (large twin-small twin) was not statistically significant (p-
value = 0.989). Consequently, no association could be demonstrated between inter-twin differences
in placental ADC and inter-twin birth weight difference. This association has, to our knowledge,
never been investigated before.
The strengths of the study are the calculation of the ADC values which includes only the highest b-
values, which means that ADC is a measure of tissue diffusion only and not a mixture of perfusion
and diffusion. Furthermore, for each placenta the ADC value is based on a ROI covering the entire
Figure 3: Scatterplot for inter-twin placental ADC differences (%) and inter-twin birth weight differences (%) with the best fitted line and confidence interval (95%).
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 17 af 52
cross-section of the placenta and calculated as a mean of five slices, which should ensure a higher
reproducibility of the method as placenta is a heterogeneous organ.
The inter-twin placental ADC difference is calculated with attention to who was the largest fetus at
birth, to make sure that the results show us which fetus has the highest ADC (inter-twin placental
ADC difference either positive or negative) and thereby if our hypothesis (higher ADC if largest
fetus) was confirmed. Previous studies 11,15–17,23,21,22,24,20,19,18,34 do not clearly state, whether their
inter-twin difference in the specific parameter (EFW, AC or others) is calculated with attention to
who was the largest fetus at birth. Since these studies focuses on fetal parameters, maybe it is
assumed that the twin with the largest measure is also the same twin that is largest at birth. This
assumption cannot be made when investigating the placenta. Dias, T. et.al35 found that 20.3 % and
5.9 % of sex discordant twins changed birth order when delivered by Cesarean section and
vaginally, respectively. If this applies to all twin pairs, the measurements at ultrasound are even
harder to correlate to the right twin – especially if they are sex concordant.
The limitations of this study are the small study population (16 twin pairs). However, the mean
inter-twin placental ADC difference was -0.03±9.45 %, very close to zero. Furthermore, the median
inter-twin birth weight differences was relatively small (median = 6.91 % (range: 0.41-29.84 %),
Table 1). There was only one discordant twin pair according to the definition (inter-twin birth
weight difference >20%). This particular twin pair showed negative inter-twin placental ADC
difference (-2.96%, Table 1), indicating a smaller placental ADC value of the larger twin. This
altogether suggests that a larger study population would not change the conclusion of this study.
In addition, the time interval between the MRI scan and birth varied between 1.7 and 16.4 weeks
(median 12.0 weeks, Table 1). However, here was no association between the time interval between
the MRI scan and inter-twin placental ADC differences. This indicates that reducing the time
interval between the MRI scan and birth would not change the conclusion of this study.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 18 af 52
This study investigates a placental cause of low birth weight, instead of measuring the outcome
(fetal parameters). This will potentially allow us to identify the placenta problem before it affects
the fetus.
In the interpretation of the placental ADC, one should consider the anatomy of the placenta. Though
it is still unclear what is exactly measured with ADC in the placenta36, the current use of ADC
values in other tissues can provides with some theories. Placenta is a heterogeneous organ,
including fluid-containing compartments such as the intervillous space, where random water
movements are relatively free 37 and therefore the placental ADC value high, but also dense tissue
(high cellularity) where the ADC value is reduced because the random water movements are
restricted. Furthermore, maturational changes (e.g. fibrosis, necrosis or infarction) in a normal
placenta can reduce the diffusion38 and the presence of calcification in tissue might also reduce the
ADC.39 Calcifications are especially common in infarctions which are closely associated with
placental insufficiency, which may explain a reduced ADC value at fetal growth restriction.
Although we try to minimize the effect from the heterogeneity in placenta on the ADC value by
including larger ROIs covering the entire placenta and by calculating the ADC value as a mean of 5
slices, we cannot reject this as a problem.
Bonel et.al.27+37,38 and Chantraine et.al.33 found lower ADC values in IUGR singleton pregnancies.
In one of the studies32,40, the placental ADC values were calculated as a straight line between the
three highest b-values and b = 0 sec/mm2. By including the b-value=0 sec/mm2 the placental
perfusion will also contribute to this measurement (ADC). In the other study33, the calculation of
ADC is not mentioned. According to our data, placental ADC is not reduced in the smaller twin
when compared to the larger co-twin. The placental ADC value in our study is based on diffusion
(b-values 200-1000 sec/mm2). Our finding indicates that it might be the perfusion rather than the
diffusion that causes the reduced placental ADC value in the FGR cases in the previous studies.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 19 af 52
Conclusion
As previously stated, there is a need of good predictors of twin discordance. However, according to
our data, placental ADC values based on diffusion only (higher b-values) is not a good predictor of
birth weight discordance in twin pregnancies.
Future placental MRI studies need to investigate placental ADC with lower b-values to isolate
perfusion as a potential placental marker for prediction of birth weight discordance in twin
pregnancies.
Litteratur 1. Patenaude Y, Pugash D, Lim K, et al. The use of magnetic resonance imaging in the obstetric patient.
J Obstet Gynaecol Can. 2014;36(4):349–55. 2. Strizek B, Jani JC, Mucyo E, et al. Safety of MR Imaging at 1.5 T in Fetuses: A Retrospective Case-
Control Study of Birth Weights and the Effects of Acoustic Noise. Radiology. 2015 May;275(2):530–7.
3. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009 Jan 21;339:b2535.
4. International Society of Prenatal Diagnosis [Internet]. Author Guidelines. [cited 2015 Dec 7]. Available from: ispdhome.org
5. Danmarks Statistik. Fødsler i Danmark [Internet]. 2015 [cited 2015 Dec 2]. Available from: https://www.dst.dk/da/Statistik/emner/foedsler/foedsler?tab=nog
6. Johansen ML, Oldenburg A, Rosthøj S, et al. Crown-rump length discordance in the first trimester: a predictor of adverse outcome in twin pregnancies? Ultrasound Obstet Gynecol. 2014;43(3):277–83.
7. D’Antonio F, Khalil A, Thilaganathan B. Second-trimester discordance and adverse perinatal outcome in twins: the STORK multiple pregnancy cohort. BJOG. 2014;121(4):422–9.
8. D’Antonio F, Khalil A, Dias T, et al. Weight discordance and perinatal mortality in twins: analysis of the Southwest Thames Obstetric Research Collaborative (STORK) multiple pregnancy cohort. Ultrasound Obstet Gynecol. 2013 Jun;41(6):643–8.
9. D’Antonio F, Khalil A, Dias T, et al. Crown-rump length discordance and adverse perinatal outcome in twins: analysis of the Southwest Thames Obstetric Research Collaborative (STORK) multiple pregnancy cohort. Ultrasound Obstet Gynecol. 2013 Jun;41(6):621–6.
10. Kaponis A, Thanatsis N, Papadopoulos V, et al. Intertwin estimated fetal weight or crown rump length discordance and adverse perinatal outcome. J Perinat Med. 2015;
11. Banks CL, Nelson SM, Owen P. First and third trimester ultrasound in the prediction of birthweight discordance in dichorionic twins. Eur J Obstet Gynecol Reprod Biol. 2008 May;138(1):34–8.
12. Reberdao MA, Martins L, Torgal M, et al. The source of error in the estimation of intertwin birth weight discordance. J Perinat Med. 2010 Nov 1;38(6):671–4.
13. Gernt PR, Mauldin JG, Newman RB, et al. Sonographic prediction of twin birth weight discordance. Obstet Gynecol. 2001 Jan;97(1):53–6.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 20 af 52
14. Machado RCA, Brizot ML, Liao AW, et al. Prenatal sonographic prediction of twin growth discordance. Twin Res Hum Genet. 2007 Feb;10(1):198–201.
15. Hoopmann M, Kagan KO, Yazdi B, et al. Prediction of Birth Weight Discordance in Twin Pregnancies by Second- and Third- Trimester Ultrasound. Fetal Diagn Ther. 2011;30(1):29–34.
16. van de Waarsenburg MK, Hack KEA, Rijpma RJ, et al. Ultrasonographic prediction of birth weight discordance in twin pregnancies. Prenat Diagn. 2015 Sep;35(9):906–12.
17. Diaz-Garcia C, Bernard JP, Ville Y, et al. Validity of sonographic prediction of fetal weight and weight discordance in twin pregnancies. Prenat Diagn. 2010 Apr;30(4):361–7.
18. Sayegh SK, Warsof SL. Ultrasonic prediction of discordant growth in twin pregnancies. Fetal Diagn Ther. 1993;8(4):241–6.
19. Chang Y-L, Chang T-C, Chang S-D, et al. Sonographic prediction of significant intertwin birth weight discordance. Eur J Obstet Gynecol Reprod Biol. 2006 Jul;127(1):35–40.
20. Khalil A, D’Antonio F, Dias T, et al. Ultrasound estimation of birth weight in twin pregnancy: comparison of biometry algorithms in the STORK multiple pregnancy cohort. Ultrasound Obstet Gynecol. 2014;44(2):210–20.
21. Weissmann-Brenner A, Weisz B, Achiron R, et al. Can discordance in CRL at the first trimester predict birth weight discordance in twin pregnancies ? J Perinat Med. 2012;40(5):489–93.
22. Kalish RB, Chasen ST, Gupta M, et al. First trimester prediction of growth discordance in twin gestations. Am J Obstet Gynecol. 2003 Sep;189(3):706–9.
23. Simoes T, Julio C, Cordeiro A, et al. Abdominal circumference ratio for the diagnosis of intertwin birth weight discordance. J Perinat Med. 2011;39(1):43–6.
24. Fajardo-Expósito MA, Hervías B, González FB, et al. First trimester fetal head and trunk volume predict growth disturbance in twin pregnancy. Prenat Diagn. 2011 Jun;31(6):543–7.
25. Sinding M, Peters DA, Frøkjaer JB, et al. Placental T2* measurements in normal pregnancies and in pregnancies complicated by fetal growth restriction. Ultrasound Obstet Gynecol. 2015 Jun 4;
26. Sohlberg S, Mulic-Lutvica A, Olovsson M, et al. Magnetic resonance imaging-estimated placental perfusion in fetal growth assessment. Ultrasound Obstet Gynecol. 2015 Dec;46(6):700–5.
27. Sohlberg S, Mulic-Lutvica A, Lindgren P, et al. Placental perfusion in normal pregnancy and early and late preeclampsia: a magnetic resonance imaging study. Placenta. 2014 Mar;35(3):202–6.
28. Geipel A, Berg C, Germer U, et al. Doppler assessment of the uterine circulation in the second trimester in twin pregnancies: prediction of pre-eclampsia, fetal growth restriction and birth weight discordance. Ultrasound Obstet Gynecol. 2002 Dec;20(6):541–5.
29. Belogolovkin V, Engel SM, Ferrara L, et al. Does Sonographic Determination of Placental Location Predict Fetal Birth Weight in Diamniotic-Dichorionic Twins? J Ultrasound Med. 2007;26:187–91.
30. Alison M, Chalouhi GE, Autret G, et al. Use of intravoxel incoherent motion MR imaging to assess placental perfusion in a murine model of placental insufficiency. Invest Radiol. 2013;48(1):17–23.
31. Moore RJ, Issa B, Tokarczuk P, et al. In vivo intravoxel incoherent motion measurements in the human placenta using echo-planar imaging at 0.5 T. Magn Reson Med. 2000;43:295–302.
32. Bonel HM, Stolz B, Diedrichsen L, et al. Diffusion-weighted MR Imaging of the Placenta in Fetuses with Placental Insufficiency1. Radiology. 2010;257(3):810–9.
33. Chantraine F, Tebache M, Passoglou V, et al. Abstracts for the International Federation of Placenta Associations Meeting 2012. Placenta. 2012 Sep;33(9):A133.
34. Blickstein I, Manor M, Levi R, et al. Is intertwin birth weight discordance predictable. Gynecol Obstet Invest. 1996;42:105–8.
35. Dias T, Ladd S, Mahsud-Dornan S, et al. Systematic labeling of twin pregnancies on ultrasound.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 21 af 52
Ultrasound Obstet Gynecol. 2011 Aug;38(2):130–3. 36. Siauve N, Chalouhi GE, Deloison B, et al. Functional imaging of the human placenta with magnetic
resonance. Am J Obstet Gynecol. Elsevier Inc.; 2015;213(4):S103–14. 37. Sener R. Diffusion MRI: apparent diffusion coefficient (ADC) values in the normal brain and a
classification of brain disorders based on ADC values. Comput Med imaging Graph. 2001;25(4):299–326.
38. Andescavage NN, Plessis A, Limperopoulos C. Advanced MR imaging of the placenta : Exploring the in utero placenta – brain connection. Semin Perinatol. Elsevier; 2015;39(2):113–23.
39. Razek AAKA, Sadek AG, Kombar OR, et al. Role of Apparent Diffusion Coefficient Values in Differentiation Between Malignant and Benign Solitary Thyroid Nodules. Am J Neuroradiol. 2008 Mar 1;29(3):563–8.
40. Sonmez G, Sivrioglu AK, Ozturk E, et al. Placental Insufficiency and Apparant Diffusion Coefficients - Letter to the Editor (Bonel, H. et.al.). Radiology. 2011;261(1):333–4.
41. Tebache M, Passoglou V, Tebache L, et al. Diffusion-Weighted MR Imaging in Placental Insufficiency: Erroneous Units and Inaccurate Apparent Diffusion Coefficient Measurements - Letter to the Editor (Bonel, H. et.al.). Radiology. 2011;260(1):303–4.
42. Overgaard C, Grundsøe MB. Fokus på informationskompetence i et tværfagligt læringsmiljø - et empirisk studie af læringseffekter og studenterperspektiver. Dansk Univ Tidsskr. 2014;9(16):124–43.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 22 af 52
Bilag
1. EpiData – Indtastningsark for “Placenta-databasen”
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 23 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 24 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 25 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 26 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 27 af 52
2. SPSS syntax Kommentarer i syntax-filen er markeret med fed. /* betyder, at teksten, der følger i den sætning, ikke tages med som kommando i SPSS.
Hermed følger den reelle syntax-tekst fra IBM SPSS Statistics, version 22.0:
/* DATA IMPORT:
GET DATA /TYPE=TXT
/FILE="STI OG FILNAVN MED DATA"
/DELCASE=LINE
/DELIMITERS=","
/QUALIFIER='"'
/ARRANGEMENT=DELIMITED
/FIRSTCASE=2
/IMPORTCASE=ALL
/VARIABLES=
ID F3.0
Singleton F1.0
DCvsMC F1.0
GA_birth DOT4.1
Sex_F1 F1.0
BW_g_F1 F4.0
Sex_F2 F1.0
BW_g_F2 F4.0
GA_MRI_S1F1 DOT4.1
P_ADC_S1F1 DOT4.2
GA_MRI_S1F2 DOT4.1
P_ADC_S1F2 DOT4.2
ID2 F3.0
GA_MRI_S2F1 DOT4.1
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 28 af 52
P_ADC_S2F1 DOT4.2
GA_MRI_S2F2 DOT4.1
P_ADC_S2F2 DOT4.2.
CACHE.
EXECUTE.
DATASET NAME DataSet2 WINDOW=FRONT.
SAVE OUTFILE='C:\Users\Ditte\Dropbox\Filer\Placenta\SPSS\Relevant_gemelli_placentadatabase_spss.sav'
/COMPRESSED.
/*KLARGØRING AF DATA, så data får korrekt antal cifre og decimaler:
/*FØDSEL
IF (GA_birth >= 100) GA_birth=GA_birth / 10.
EXECUTE.
/*MR skanning
IF (GA_MRI_S1F1 >= 100) GA_MRI_S1F1=GA_MRI_S1F1 / 10.
EXECUTE.
IF (GA_MRI_S1F2 >= 100) GA_MRI_S1F2=GA_MRI_S1F2 / 10.
EXECUTE.
IF (GA_MRI_S2F1 >= 100) GA_MRI_S2F1=GA_MRI_S2F1 / 10.
EXECUTE.
IF (GA_MRI_S2F2 >= 100) GA_MRI_S2F2=GA_MRI_S2F2 / 10.
EXECUTE.
/*ADC
IF (P_ADC_S1F1 >=100) P_ADC_S1F1 = P_ADC_S1F1 /100.
EXECUTE.
IF (P_ADC_S1F2 >=100) P_ADC_S1F2 = P_ADC_S1F2 /100.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 29 af 52
EXECUTE.
IF (P_ADC_S2F1 >=100) P_ADC_S2F1 = P_ADC_S2F1 /100.
EXECUTE.
IF (P_ADC_S2F2 >=100) P_ADC_S2F2 = P_ADC_S2F2 /100.
EXECUTE.
IF (P_ADC_S1F1 >=10) P_ADC_S1F1 = P_ADC_S1F1 /10.
EXECUTE.
IF (P_ADC_S1F2 >=10) P_ADC_S1F2 = P_ADC_S1F2 /10.
EXECUTE.
IF (P_ADC_S2F1 >=10) P_ADC_S2F1 = P_ADC_S2F1 /10.
EXECUTE.
IF (P_ADC_S2F2 >=10) P_ADC_S2F2 = P_ADC_S2F2 /10.
EXECUTE.
/* Fjern ID 61 og ID 135, hhv. ikke med i DWI-protokol (ID 61) og kontraktion under DWI-skanning (ID 135):
DATASET ACTIVATE DataSet2.
SELECT IF NOT ANY (ID, 61, 135).
EXECUTE.
/* Fjern ID numre, der endnu ikke har født ( i alt 8 tvillinge-par):
DATASET ACTIVATE DataSet2.
SELECT IF (GA_birth > 0).
EXECUTE.
/* Overfør gemelli-cases (der ikke er ekskluderet ovenfor) til nyt dataark:
DATASET ACTIVATE DataSet2.
DATASET COPY Gemelli_dataset.
DATASET ACTIVATE Gemelli_dataset.
FILTER OFF.
USE ALL.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 30 af 52
SELECT IF (Singleton = 0).
EXECUTE.
SORT CASES BY ID(A).
/* Gestationsalder ved MR skanning samles i én variabel (med gestationsalder for første MR-skanning i DWI protokol - ID 66 og 67 er først inkluderet i DWI protokol ved anden MR-skanning):
DATASET ACTIVATE Gemelli_dataset.
COMPUTE GA_MRI = GA_MRI_S1F2.
EXECUTE.
IF missing (P_ADC_S1F1) GA_MRI = GA_MRI_S2F2.
EXECUTE.
FORMATS GA_MRI(f2.1).
EXECUTE.
/*Gestationsalder mellem fødsel og MR:
DATASET ACTIVATE Gemelli_dataset.
COMPUTE GA_MRI_birth = GA_birth - GA_MRI.
EXECUTE.
FORMATS GA_MRI_birth(f2.1).
EXECUTE.
/* Saml ADC-værdier fra første MR skanning i DWI protokol til én variabel - ID 66 og 67 er først inkluderet i DWI protokol ved anden MR-skanning:
DATASET ACTIVATE Gemelli_dataset.
COMPUTE P_ADC_F1=P_ADC_S1F1.
EXECUTE.
IF missing (P_ADC_S1F1) P_ADC_F1=P_ADC_S2F1.
EXECUTE.
COMPUTE P_ADC_F2=P_ADC_S1F2.
EXECUTE.
IF missing (P_ADC_S1F2) P_ADC_F2=P_ADC_S2F2.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 31 af 52
EXECUTE.
FORMATS P_ADC_F1(f3.2).
EXECUTE.
FORMATS P_ADC_F2(f3.2).
EXECUTE.
/*INTER-TWIN BEREGNINGER:
/*Beregning af intertwin forskel i fødselsvægt i procent (nævner = højeste fødselsvægt):
DATASET ACTIVATE Gemelli_dataset.
IF (BW_g_F1 > BW_g_F2) BW_larger_twin = BW_g_F1.
EXECUTE.
IF (BW_g_F2 > BW_g_F1) BW_larger_twin = BW_g_F2.
EXECUTE.
FORMATS BW_larger_twin(f4.0).
EXECUTE.
IF (BW_g_F1 > BW_g_F2) BW_smaller_twin = BW_g_F2.
EXECUTE.
IF (BW_g_F2 > BW_g_F1) BW_smaller_twin = BW_g_F1.
EXECUTE.
FORMATS BW_smaller_twin(f4.0).
EXECUTE.
COMPUTE Intertwin_BW_procent = (BW_larger_twin - BW_smaller_twin) / BW_larger_twin * 100.
EXECUTE.
/* Beregning af Inter-twin ADC forskel i procent (nævner = højeste ADC) - ADC for mindste tvilling trækkes fra ADC for største tvilling og divideres med højeste ADC:
DATASET ACTIVATE Gemelli_dataset.
IF (BW_g_F1 > BW_g_F2) ADC_larger_twin=P_ADC_F1.
EXECUTE.
IF (BW_g_F2 > BW_g_F1) ADC_larger_twin=P_ADC_F2.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 32 af 52
EXECUTE.
IF (BW_g_F1 > BW_g_F2) ADC_smaller_twin=P_ADC_F2.
EXECUTE.
IF (BW_g_F2 > BW_g_F1) ADC_smaller_twin=P_ADC_F1.
EXECUTE.
IF ( P_ADC_F1 > P_ADC_F2) Intertwin_percent_ADC = (ADC_larger_twin - ADC_smaller_twin) / P_ADC_F1 *100.
EXECUTE.
IF (P_ADC_F2 > P_ADC_F1) Intertwin_percent_ADC = (ADC_larger_twin - ADC_smaller_twin) / P_ADC_F2 * 100.
EXECUTE.
/* Navngiv variable:
DATASET ACTIVATE Gemelli_dataset.
* Define Variable Properties.
*Singleton.
VALUE LABELS Singleton
0 'twin'
1 'singleton'.
*DCvsMC.
VALUE LABELS DCvsMC
1 'dichorionic'
2 'monochorionic'.
EXECUTE.
*GA_birth.
VARIABLE LABELS GA_birth 'Gestational age at birth (weeks)'.
*GA_MRI.
VARIABLE LABELS GA_MRI 'Gestational age at MRI (weeks)'.
*GA_MRI_birth.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 33 af 52
VARIABLE LABELS GA_MRI_birth 'Time between MRI and birth (weeks)'.
*ADC_larger_twin.
VARIABLE LABELS ADC_larger_twin 'ADC - larger twin (s/mm^2)'.
*ADC_smaller_twin.
VARIABLE LABELS ADC_smaller_twin 'ADC - smaller twin (s/mm^2)'.
*BW_larger_twin.
VARIABLE LABELS BW_larger_twin 'BW - larger twin (g)'.
*BW_smaller_twin.
VARIABLE LABELS BW_smaller_twin 'BW - smaller twin (g)'.
*Intertwin_BW_procent.
VARIABLE LABELS Intertwin_BW_procent 'Inter-twin birth weight difference (%)'.
*Intertwin_percent_ADC.
VARIABLE LABELS Intertwin_percent_ADC 'Inter-twin placental ADC difference (%)'.
EXECUTE.
/* Kolmogorov-Smirnov og Shapiro-Wilk - test for normality, inkl. histogram og Q-Q-plots:
DATASET ACTIVATE Gemelli_dataset.
EXAMINE VARIABLES=Intertwin_BW_procent Intertwin_percent_ADC GA_MRI_birth
/PLOT HISTOGRAM NPPLOT
/STATISTICS DESCRIPTIVES
/CINTERVAL 95
/MISSING LISTWISE
/NOTOTAL.
/*Study population characteristics, table 1
DATASET ACTIVATE Gemelli_dataset.
* Custom Tables.
CTABLES
/VLABELS VARIABLES=GA_MRI ADC_larger_twin ADC_smaller_twin Intertwin_percent_ADC GA_birth BW_larger_twin BW_smaller_twin
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 34 af 52
Intertwin_BW_procent GA_MRI_birth
DISPLAY=LABEL
/TABLE BY GA_MRI [S][MEAN, STDDEV, MEDIAN, RANGE, MINIMUM, MAXIMUM, TOTALN F40.0] + ADC_larger_twin
[S][MEAN, STDDEV, MEDIAN, RANGE, MINIMUM, MAXIMUM, TOTALN F40.0] + ADC_smaller_twin [S][MEAN, STDDEV,
MEDIAN, RANGE, MINIMUM, MAXIMUM, TOTALN F40.0] + Intertwin_percent_ADC [S][MEAN, STDDEV, MEDIAN,
RANGE, MINIMUM, MAXIMUM, TOTALN F40.0] + GA_birth [S][MEAN, STDDEV, MEDIAN, RANGE, MINIMUM,
MAXIMUM, TOTALN F40.0] + BW_larger_twin [S][MEAN, STDDEV, MEDIAN, RANGE, MINIMUM, MAXIMUM, TOTALN F40.0] +
BW_smaller_twin [S][MEAN, STDDEV, MEDIAN, RANGE, MINIMUM, MAXIMUM, TOTALN F40.0] + Intertwin_BW_procent
[MEAN, STDDEV, MEDIAN, RANGE, MINIMUM, MAXIMUM, TOTALN F40.0] + GA_MRI_birth [S][MEAN, STDDEV,
MEDIAN, RANGE, MINIMUM, MAXIMUM, TOTALN F40.0]
/SLABELS POSITION=ROW.
/* One sample t-test - tjek om der er forskel på placental ADC for larger vs. smaller twin:
/* ved at bruge variablen "inter_twin" har jeg allerede parret værdierne (i stedet for paired t-test med ADC_larger twin mod ADC_smaller twin).
DATASET ACTIVATE Gemelli_dataset.
T-TEST
/TESTVAL=0
/MISSING=ANALYSIS
/VARIABLES=Intertwin_percent_ADC
/CRITERIA=CI(.95).
/* Lineær regression Inter-twin placental ADC difference (%) og Inter-twin birth weight difference (%):
DATASET ACTIVATE Gemelli_dataset.
GRAPH
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 35 af 52
/SCATTERPLOT(BIVAR)=Intertwin_percent_ADC WITH Intertwin_BW_procent
/MISSING=LISTWISE.
DATASET ACTIVATE Gemelli_dataset.
REGRESSION
/MISSING LISTWISE
/STATISTICS COEFF OUTS R ANOVA
/CRITERIA=PIN(.05) POUT(.10)
/NOORIGIN
/DEPENDENT Intertwin_BW_procent
/METHOD=ENTER Intertwin_percent_ADC
/SCATTERPLOT=(*ZPRED ,*ZRESID)
/RESIDUALS HISTOGRAM(ZRESID) NORMPROB(ZRESID).
/*Pearson's Correlation:
DATASET ACTIVATE Gemelli_dataset.
CORRELATIONS
/VARIABLES=Intertwin_BW_procent Intertwin_percent_ADC
/PRINT=TWOTAIL NOSIG
/MISSING=PAIRWISE.
/*Lineær regression line and confidence interval:
/*Gå til output, dobbelt-klik på scatterplot, "Elements", "Fit line in total" -> Vælg "linear" og "individual, 95 %" samt fjern flueben ved "Attach regression to line" -> Tryk "apply" og luk boksen.
/* Scatterplot og lineær regression med Inter-twin ADC difference (%) og time between MRI and birth (weeks) – undersøg om forskellen i ADC kunne være afhængig af skanningstidspunkt:
DATASET ACTIVATE Gemelli_dataset.
GRAPH
/SCATTERPLOT(BIVAR)=GA_MRI_birth WITH Intertwin_percent_ADC
/MISSING=LISTWISE.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 36 af 52
/*Gem dataark:
SAVE TRANSLATE OUTFILE='STI OG FILNAVN NOTERES HER'
/TYPE=XLS
/VERSION=12
/MAP
/REPLACE
/FIELDNAMES
/CELLS=LABELS
/DROP=Singleton DCvsMC ID2.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 37 af 52
3. Litteratursøgning: Twin discordance
A. Søgeprotokol
Søgeprotokollen er baseret på ”Bilag 1: Søgebilag. Standardbilag til beskrivelse og dokumentation af informationssøgning og –udvægelse” fra Overgaard og Buje42.
1. Hypotese In dichorionic twin pregnancy, birth weight discordance can be predicted.
2. Søgeskema PUBMED:
EMBASE:
3. Søgeresultater
PUBMED:
Søgekombinationer – baseret på blok-skemaet ovenfor (punkt 2. Søgeskema) Antal hits #1: BLOK 1 1.868 #2: BLOK 2 1.087.275 #3: BLOK 3 357 #4: BLOK 4 35.136 #5: BLOK 1 AND BLOK 2 176 #6: BLOK 1 AND BLOK 3 89
AND BLOKNAVN
BLOK 1 Pregnancy, twin [MeSH]
BLOK 2 ”Predict*” [tiab]
BLOK 3 ”twin discordance*” [tiab]
BLOK 4 Birth weight [MeSH]
OR
”Dichorionic*”[tiab] ”intertwin*” [tiab] ”dichorionic twin*”[tiab]
”inter-twin*”[tiab]
”inter twin*”[tiab]
AND BLOK NAVN
BLOK 1 Exp Twin pregnancy/ (Emtree)
BLOK 2 Predict*.mp.
BLOK 3 Exp Twin discordance/ (Emtree)
BLOK 4 Exp Birth weight/ (Emtree)
OR
”Dichorionic*”.mp. ”intertwin*”.mp. ”dichorionic twin*”.mp.
”inter-twin*”.mp
”inter twin*”.mp
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 38 af 52
#7: BLOK 1 AND BLOK 4 177 #8: BLOK 1 AND BLOK 2 AND BLOK 3 23 #9: BLOK 2 AND BLOK 3 AND BLOK 4 24 #10: BLOK 1 AND BLOK 2 AND BLOK 3 AND BLOK 4 8
EMBASE:
Søgekombinationer – baseret på blok-skemaet ovenfor (punkt 2. Søgeskema) Antal hits #1: BLOK 1 9.112 #2: BLOK 2 1.437.616 #3: BLOK 3 1.803 #4: BLOK 4 88.952 #5: BLOK 1 AND BLOK 2 780 #6: BLOK 1 AND BLOK 3 513 #7: BLOK 1 AND BLOK 4 1.533 #8: BLOK 1 AND BLOK 2 AND BLOK 3 103 #9: BLOK 2 AND BLOK 3 AND BLOK 4 76 #10: BLOK 1 AND BLOK 2 AND BLOK 3 AND BLOK 4 50
4. Kriterier for udvælgelse af relevant litteratur: a. Titel relevant for forskningshypotese. b. Abstract relevant for forskningshypotese. c. Fuldtekst tilgængelig. d. Fuldtekst relevant for forskningshypotese. e. Evidensniveau (minimum grade III).
Humane studier (ikke dyr) og artikler på sprogene (dansk, engelsk, norsk eller svensk) er accepteret. Artikler, der ikke opfylder disse kriterier, fjernes fra søgningen.
6. Dato og identifikation
Søgningen blev gennemført d. 26. november 2015 af Ditte Nymark Hansen, lægestuderende, 11. semester, Aalborg Universitet.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 39 af 52
B. Flowdiagram for søgning Baseret på “PRISMA 2009 Flow Diagram” 3.
Resultaterne i flowdiagrammet er fra søgningen gennemgået ovenfor (Appendix, 3. Litteratursøgning: Twin discordance, A. Søgeprotokol).
PubMed: (”Pregnancy, twin”[MeSH] OR ”dichorionic*”[tiab] OR ”dichorionic twin*”[tiab]) AND ((predict*[tiab]) AND (”twin discordance*”[tiab] OR ”intertwin*”[tiab] OR ”inter-twin*”[tiab] OR ”inter twin*”[tiab]) AND ”birth weight”[MeSH])
Embase: (”exp Twin pregnancy/” OR ”dichorionic*”.mp. OR ”dichorionic twin*”.mp.) AND (predict*.mp. AND (”exp twin discordance/” OR (”intertwin”.mp. OR “inter-twin*”.mp. OR “inter twin*”.mp.)) AND ”exp birth weight/”)
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 40 af 52
C. Review-tabel
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 41 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 42 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 43 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 44 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 45 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 46 af 52
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 47 af 52
4. Litteratursøgning: Diffusion-Weighted Imaging
A. Søgeprotokol Søgeprotokollen er baseret på ”Bilag 1: Søgebilag. Standardbilag til beskrivelse og dokumentation af informationssøgning og –udvægelse” fra Overgaard og Buje42.
1. Hypotese In pregnancy is lower placental diffusion on DWI MRI associated with lower birth weight/placental insufficiency (defined by fetal weight)
- Tvillinge-specifik hypotese:
In dichorionic twin pregnancy is lower birth weight in at least one of the twins associated with lower placental diffusion on DWI MRI?
2. Søgeskema PUBMED:
AND BLOK-NAVN
BLOK 1 Placenta [MeSH]
BLOK 2 Pregnancy, twin [MeSH]
BLOK 3 Diffusion magnetic resonance imaging [MeSH]
BLOK 4 ”Apparent diffusion coefficient” [tiab]
BLOK 5 Fetal weight [MeSH]
BLOK 6 Birth weight [MeSH]
BLOK 7 Fetal growth retardation [MeSH]
OR
”DWI” [tiab]
”ADC” [tiab]
”FGR” [tiab]
”Intra uterine growth restriction” [tiab]
Placental insuffi-ciency [MeSH]
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 48 af 52
EMBASE: AND BLOK-NAVN
BLOK 1 Placenta (Emtree)
BLOK 2 Twin preg-nancy (Emtree)
BLOK 3 Diffusion weighted imaging (Emtree)
BLOK 4 ”Apparent diffusion coefficient” .tiab.
BLOK 5 Fetus weight (Emtree)
BLOK 6 Birth weight (Emtree)
BLOK 7 Intrauterine growth retardation (Emtree)
OR
”DWI” ”ADC” ”intra uterine growth restriction”
”IUGR” ”FGR” Placenta
insufficiency (Emtree)
3. Søgeresultater
PUBMED:
Søgekombinationer – baseret på blok-skemaet ovenfor (punkt 2. Søgeskema) Antal hits # 1: Blok 1 58.046 # 2: Blok 2 1.113 # 3: Blok 3 14.931 # 4: Blok 4 9.209 # 5: Blok 5 1.299 # 6: Blok 6 35.128 # 7: Blok 7 15.241 # 8: Blok 3 AND Blok 4 4.229 # 9: Blok 1 AND Blok 3 9 # 10: Blok 1 AND Blok 4 5 # 11: Blok 1 AND Blok 3 AND Blok 4 2 # 12: Blok 1 AND Blok 3 AND Blok 5 1 # 13: Blok 1 AND Blok 3 AND Blok 6 0 # 14: Blok 1 AND Blok 3 AND Blok 7 2 # 15: Blok 1 AND Blok 4 AND Blok 5 0 # 16: Blok 1 AND Blok 4 AND Blok 6 0 # 17: Blok 1 AND Blok 4 AND Blok 7 0 # 18: Blok 2 AND Blok 3 2 # 19: Blok 2 AND Blok 4 0 # 20: Blok 2 AND Blok 3 AND Blok 4 0 # 21: Blok 2 AND Blok 3 AND Blok 5 0 # 22: Blok 2 AND Blok 3 AND Blok 6 0 # 23: Blok 2 AND Blok 3 AND Blok 7 0 # 24: Blok 2 AND Blok 4 AND Blok 5 0 # 25: Blok 2 AND Blok 4 AND Blok 6 0 # 26: Blok 2 AND Blok 4 AND Blok 7 0
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 49 af 52
EMBASE:
Søgekombinationer – baseret på blok-skemaet ovenfor (punkt 2. Søgeskema) Antal hits # 1: Blok 1 64.791 # 2: Blok 2 8.577 # 3: Blok 3 23.739 # 4: Blok 4 27.236 # 5: Blok 5 5.723 # 6: Blok 6 88.952 # 7: Blok 7 35.474 # 8: Blok 3 AND Blok 4 5.507 # 9: Blok 1 AND Blok 3 30 # 10: Blok 1 AND Blok 4 71 # 11: Blok 1 AND Blok 3 AND Blok 4 12 # 12: Blok 1 AND Blok 3 AND Blok 5 0 # 13: Blok 1 AND Blok 3 AND Blok 6 2 # 14: Blok 1 AND Blok 3 AND Blok 7 11 # 15: Blok 1 AND Blok 4 AND Blok 5 0 # 16: Blok 1 AND Blok 4 AND Blok 6 10 # 17: Blok 1 AND Blok 4 AND Blok 7 16 # 18: Blok 2 AND Blok 3 5 # 19: Blok 2 AND Blok 4 32 # 20: Blok 2 AND Blok 3 AND Blok 4 0 # 21: Blok 2 AND Blok 3 AND Blok 5 0 # 22: Blok 2 AND Blok 3 AND Blok 6 0 # 23: Blok 2 AND Blok 3 AND Blok 7 0 # 24: Blok 2 AND Blok 4 AND Blok 5 2 # 25: Blok 2 AND Blok 4 AND Blok 6 7 # 26: Blok 2 AND Blok 4 AND Blok 7 2
4. Kriterier for udvælgelse af relevant litteratur: a. Titel relevant for forskningshypotese. b. Abstract relevant for forskningshypotese. c. Fuldtekst tilgængelig. d. Fuldtekst relevant for forskningshypotese. e. Evidensniveau (minimum grade III).
Humane studier (ikke dyr) og artikler på sprogene (dansk, engelsk, norsk eller svensk) er accepteret. Artikler, der ikke opfylder disse kriterier, fjernes fra søgningen.
5. Dato og identifikation
Søgningen blev gennemført d. 26. november 2015 af Ditte Nymark Hansen, lægestuderende, 11. semester, Aalborg Universitet.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 50 af 52
B. Flowdiagram for søgning Baseret på “PRISMA 2009 Flow Diagram” 3.
Resultaterne i flowdiagrammet er fra søgningen gennemgået ovenfor (Appendix, 4. Litteratursøgning: Diffusion-Weighted Imaging, A. Søgeprotokol). Kasserne er baseret på bloksøgningerne ovenfor. Søgningerne med 0 hits i begge databaser er ikke med i flowdiagrammet. Kun søgninger med mindst 1 hit i minimum én af databaserne og søgninger med <1000 hits er medtaget herunder.
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 51 af 52
C. Review-tabel
Aalborg Universitet ǀ Ditte Nymark Hansen
Side 52 af 52