Ditte Nymark Hansen Placental diffusion estimated by MRI ... · isse-hale-længde (crown-rump length, CRL), abdominal omfang (AC) og estimeret føtal vægt (EFW) er associeret med,

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


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.


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 %.


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


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.


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



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


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


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.


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


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


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.


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


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).


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).


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%).


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.


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.


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.


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.


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.


Side 22 af 52

Bilag

1. EpiData – Indtastningsark for “Placenta-databasen”


Side 23 af 52


Side 24 af 52


Side 25 af 52


Side 26 af 52


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


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.


EXECUTE.


EXECUTE.


EXECUTE.

/*ADC

IF (P_ADC_S1F1 >=100) P_ADC_S1F1 = P_ADC_S1F1 /100.

EXECUTE.



Side 29 af 52

EXECUTE.


EXECUTE.


EXECUTE.


EXECUTE.


EXECUTE.


EXECUTE.


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):


SELECT IF (GA_birth > 0).

EXECUTE.

/* Overfør gemelli-cases (der ikke er ekskluderet ovenfor) til nyt dataark:


DATASET COPY Gemelli_dataset.

DATASET ACTIVATE Gemelli_dataset.

FILTER OFF.

USE ALL.


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):


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:


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:


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.


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):


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:


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.


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:


* 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.


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:


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


* Custom Tables.

CTABLES

/VLABELS VARIABLES=GA_MRI ADC_larger_twin ADC_smaller_twin Intertwin_percent_ADC GA_birth BW_larger_twin BW_smaller_twin


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).


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 (%):


GRAPH


Side 35 af 52

/SCATTERPLOT(BIVAR)=Intertwin_percent_ADC WITH Intertwin_BW_procent

/MISSING=LISTWISE.


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:


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:


GRAPH

/SCATTERPLOT(BIVAR)=GA_MRI_birth WITH Intertwin_percent_ADC

/MISSING=LISTWISE.


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.


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


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.


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/”)


Side 40 af 52

C. Review-tabel


Side 41 af 52


Side 42 af 52


Side 43 af 52


Side 44 af 52


Side 45 af 52


Side 46 af 52


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]


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


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.


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.


Side 51 af 52

C. Review-tabel


Side 52 af 52

Documents

Ditte Nymark Hansen Placental diffusion estimated by MRI ... · isse-hale-længde (crown-rump length, CRL), abdominal omfang (AC) og estimeret føtal vægt (EFW) er associeret med,