uog journal club: meta-analysis of second-trimester markers for trisomy 21

UOG Journal Club: March 2013Meta-analysis of second-trimester markers for trisomy 21

M. Agathokleous, P. Chaveeva, L. C. Y. Poon, P. Kosinksi and K. H. NicolaidesVolume 41, Issue 3, Date: March 2013, pages 247–261

Journal Club slides prepared by Dr Asma Khalil(UOG Editor for Trainees)

Trachea

ARSA

Spine

Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013

Second-trimester markers for trisomy 21

• Ventriculomegaly

• Absent or hypoplastic nasal bones

• Increased nuchal fold thickness

• Intracardiac echogenic focus

• Aberrant right subclavian artery

• Echogenic bowel

• Mild hydronephrosis

• Shortening of femur or humerus


Normal Tr 21 LR+ LR-

Mild hydronephrosis 2.6% 17.1% 6.8 0.85Echogenic foci 4.4% 30.3% 6.4 0.75Short femur 5.2% 42.0% 7.9 0.62Echogenic bowel 0.6% 17.3% 21.2 0.87Nuchal fold >6 mm 0.6% 41.1% 53.1 0.67Major defect 0.7% 21.4% 33.0 0.79

LRc*

1.01.01.53.0

10.05.0

Nicolaides UOG 2003, Nyberg et al. Ultrasound Med 2001

Background risk x LR of each marker

Calculation of risk for trisomy 21

Individual risk = a priori risk × LR1 × LR2 × LR3…

LRc* = LR isolated marker


Examine the screening performance of second trimester sonographic markers for the detection of trisomy 21

Objective


• Studies reporting on the incidence of one or more markers in trisomy 21 and euploid fetuses

• 1995 – September 2012

• GA at examination14-24 wk

1. 2 × 2 tables for diagnostic performance could be constructed

2. Karyotype was unknown at the time of ultrasound

3. Chromosomal status was confirmed by karyotype or postnatal examination

Methodology

Inclusion criteria Eligibility criteria

• Prospective and retrospective cohort studies • Case–control studies (for ARSA and absent/hypoplastic nasal bones)

• Methodological quality of the studies: Newcastle–Ottawa scale

• Weighted independent estimation of DR, FPR, +ve LR (sensitivity/(1−specificity)) and –ve LR ((1−sensitivity)/specificity)

• Heterogeneity between studies: Higgins’ I2 and Q-test

• Explore the effect of heterogeneity: analysis for the whole dataset and in the subgroups (high risk and screening)


Methodology

• Ventriculomegaly: ≥ 10 mm• Increased nuchal fold thickness: ≥ 6 mm • Echogenic bowel: equal echogenicity to that of bone• Mild hydronephrosis: renal pelvis AP diameter varied from 3 to 4 or 5 mm• Hypoplastic nasal bones: cut-off varied with gestation• Short femur or humerus: cut-off varied with gestation


Results

Definitions of the markers

Trachea

ARSA

Spine

Meta-analysis 47 studies 1995–2012

Marker DR FPR LRLR+ ve+ ve

LRLR– – veve

Isolatedmarker

Cardiac echogenic focus 24.4 3.9 5.85.8 0.800.80 0.95

Ventriculomegaly 7.5 0.2 27.527.5 0.940.94 3.81

Increased nuchal fold 26.0 1.0 23.323.3 0.800.80 3.79

Echogenic bowel 16.7 1.1 11.411.4 0.900.90 1.65

Mild hydronephrosis 13.9 1.7 7.67.6 0.920.92 1.08

Short humerus 30.3 4.6 4.84.8 0.740.74 0.78

Short femur 27.7 6.4 3.73.7 0.800.80 0.61

ARSA 30.7 1.5 21.521.5 0.710.71 3.94

Absent or hypoplastic NB 59.8 2.8 23.323.3 0.460.46 6.58


No markers LR 0.13 = 7.7 fold reduction

Estimation of combined LR of multiple markers

•The LR for trisomy 21 of individual isolated markers is derived by multiplying the +ve LR for the given marker by the –ve LR of each of all other markers

• The same approach when any combination of ≥ two markers are detected e.g. with mild hydronephrosis (+ve LR 7.6) and ventriculomegaly (+ve LR 27.5), the combined +ve LR is 209 (7.6 × 27.5). This must be multiplied by the combined -ve LR of all other markers that were not present (0.8 × 0.8 × 0.9 × 0.8 × 0.7 × 0.5 = 0.2) to derive a final combined LR of 31.6


Results


MarkerPresent/Absent (choose from drop-down: Present/Absent/Not known) LR

Intracardiac echogenic focus Not known 1.00Mild hydronephrosis Not known 1.00Short femur Not known 1.00Echogenic bowel Not known 1.00Increased nuchal fold Not known 1.00Aberrant right subclavian artery Not known 1.00Absent or hypoplastic nasal bone Not known 1.00Ventriculomegaly Not known 1.00

LR for combination: 1.00

http://onlinelibrary.wiley.com/doi/10.1002/uog.12364/suppinfo

ResultsExcel spreadsheet (online) allowing automated calculations of the LR for

any given combination of the presence and absence of markers


a) Echogenic foci

b) Ventriculomegaly

c) Nuchal fold thickness

d) Echogenic bowel

e) Hydronephrosis

f) Short humerus

g) Short femur

h) ARSA

i) Absent nasal bone

j) Absent or hypoplastic

nasal bone

Results

Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks Ashoor et al., UOG 2013

Discussion

• Heterogeneity in results between the studies explained by differences in design and focus of individual studies

• The problem of high heterogeneity was not overcome by sub-analysis of data (screening versus high-risk populations)

• Studies published before 1995 were excluded (limited awareness)

• GA 14–24 weeks: potential effect of GA on the incidence of the markers

• The majority of the included studies only examined the value of individual markers. There are no studies that systematically examined the possible interrelationship between markers, and it is therefore assumed that they are independent of each other, apart from short femur and humerus


Implications for practice

1. There is a 7.7-fold reduction in risk for trisomy 21 if a systematic second-trimester ultrasound examination demonstrates the absence of all markers

2. The detection of any one of the markers during the scan should alert the sonographer to look for all other markers

3. The post-test odds is derived by multiplying the pre-test odds by the +ve LR for each detected marker and the -ve LR for each marker demonstrated to be absent

4. There is only a small effect on modifying the pre-test odds in the case of most isolated markers (echogenic focus, echogenic bowel, mild hydronephrosis and short femur)


Conclusions

• The data from this meta-analysis and their interpretation could guide clinical practice.

• However, appropriate training, certification and regular audit are essential.

uog journal club: meta-analysis of second-trimester markers for trisomy 21

Health & Medicine

mild hydronephrosis

ve lr

ve lr

echogenic

short femur

test odds

trisomy 21agathokleous

trimester