Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.23616
ISUOG Practice Guidelines (updated): sonographic examination of the fetal central nervous system. Part 2: performance of targeted neurosonography
Clinical Standards CommitteeThe International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, and high-quality teaching and research related to diagnostic imaging in women’s healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach, from experts, for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practice at the time at which they are issued. Although ISUOG has made every effort to ensure that Guidelines are accurate when issued, neither the Society nor any of its employees or members accepts any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. The ISUOG CSC documents are not intended to establish a legal standard of care, because interpretation of the evidence that underpins the Guidelines may be influenced by individual circumstances, local protocol and available resources. Approved Guidelines can be distributed freely with the permission of ISUOG ([email protected]). Details of the grades of recommendation and levels of evidence used in ISUOG Guidelines are given in Appendix 1.
INTRODUCTION
Central nervous system (CNS) malformations are some of the most common congenital abnormalities, with an incidence at birth of 14/10 000 1. Neural tube defects are themost frequent CNSmalformation, with a prevalence in pregnancy of 52/100 0002. The incidence of intracranial abnormalities with an intact neural tube is uncertain, as most of these abnormalities are likely to escape detection at birth andmanifest only in later life. Long-term follow-up studies suggest, however, that the incidence may be as high as one in 100 births3. During pregnancy, ultrasound screening for CNS malformations is carried out mainly at the time of the mid-trimester anomaly scan4 and relies on visualization of three axial planes, namely, the transventricular, transthalamic and transcerebellar planes; basic evaluation of the fetal spine is also part of this screening procedure, and has been described in Part 1 of these guidelines5. However, of note is that some malformations may be detectable as early as the first-trimester scan. The focus of this Guideline is to describe the protocol for the diagnostic ultrasound examination that should be performed in any case in which there is an increased risk of CNS malformation. A detailed list of indications for this targeted fetal neurosonography was published in Part 1 of these guidelines5. It is commonly accepted that targeted fetal neurosonography has a much greater diagnostic potential than does the basic screening examination, and is particularly helpful in the evaluation of complex malformations6,7. However, this targeted examination of the fetal CNS requires a high level of expertise that is not always available in many ultrasound facilities, since the method has not yet been implemented universally.
GENERAL CONSIDERATIONS
Recommendation
- The transvaginal approach is the preferred method to perform an adequate high-resolution targeted neurosonographic examination. When this is not technically feasible (e.g. breech presentation; twin pregnancy), the examination is performed transabdominally (GOOD PRACTICE POINT).
- When a transvaginal approach is not technically feasible, the use of high-resolution linear or microconvex transducers (i.e.multiband emission frequency reaching 8–9MHz) is encouraged, because these provide higher resolution than do conventional convex probes (GOOD PRACTICE POINT).
The basis of the neurosonographic examination of the fetal brain is the multiplanar approach, which is obtained by aligning the transducer with the sutures and fontanelles of the fetal head8–10. When the fetus is in vertex presentation, a transvaginal approach should always be used, because it provides significant advantages over the transabdominal one. In particular, this approach allows both higher resolution, due to the higher emission frequency, and an unobstructed display of sagittal and coronal planes, as the acoustic shadowing produced by the calvarium is circumvented. In fetuses in breech presentation, a transfundal approach is used, positioning the probe on the uterine fundus, parallel instead of perpendicular to the abdomen. However, gentle external version, performed in conjunction with ultrasound examination, is often possible until the early third trimester and should be attempted when technically feasible11. Evaluation of the spine is also part of the neurosonographic examination, and this is performed using a combination of axial, coronal and sagittal planes, as described in Part 1 of these guidelines5. During the neurosonographic examination of the spine, the position of the conus medullaris is assessed in the sagittal plane. The neurosonographic examination should include the same measurements as those commonly obtained during a basic examination: biparietal diameter, head circumference, atrial width of the lateral ventricles and the transverse cerebellar diameter. The anteroposterior diameter of the cisterna magna is not measured routinely; it should be measured only if there is suspicion of megacisterna magna. Many nomograms of different brain structures are available and can be used when needed10,12. The specific measurements obtained may vary depending upon the gestational age and the clinical setting.
NEUROSONOGRAPHIC TECHNIQUE
Fetal brain
Whether the examination is performed transvaginally
or transabdominally, proper alignment of the probe
along the correct section planes usually requires gentle
manipulation of the fetus. A variety of scanning planes
can be used, depending upon the position of the fetus10.
A systematic evaluation of the brain usually includes
visualization of four coronal and three sagittal planes. We
present herein a description of the different structures that
can be imaged in the second and third trimesters. Apart
from the anatomic structures, fetal neurosonography
should also include evaluation of the convolutions of
the fetal brain, which change throughout gestation13–17.
- Targeted anatomic assessment of the fetal brain relies on a continuum of sagittal and coronal planes. The key planes are described below, but the trained operator should be able to choose and document those most suited to demonstrating normal/abnormal anatomy (GOOD PRACTICE POINT).
Transfrontal plane (Figure 1a). Visualization of the transfrontal
plane is through the anterior fontanelle. It depicts the midline interhemispheric fissure and the frontal lobes
of the brain. The plane is anterior to the corpus callosum
and therefore demonstrates an uninterrupted interhemispheric
fissure. Other structures that appear on the image
are the sphenoid bone and, sometimes, the orbits. Late in
gestation, the olfactory sulci are also visible15,18 (Figure 2).
Transcaudate plane (Figure 1b). The transcaudate
plane is obtained through a more posterior approach,
tilting and/or sliding the transducer towards the posterior
edge of the anterior fontanelle. It is one of the most
important views in fetal neurosonography. It shows:
the frontal horns of the lateral ventricles; the cavum
septi pellucidi (a triangular/trapezoid structure below
the corpus callosum and between the two frontal horns);
the cross-section of the anterior part of the body of the
corpus callosum, appearing as a mildly hypoechoic band
on top of the cavum septi pellucidi and between the
frontal horns; the cerebral falx; the ganglionic eminence;
and the caudate nuclei.
Transthalamic plane (Figure 1c). The transthalamic
plane is relatively close to the transcaudate plane. It is
obtained sometimes through the anterior fontanelle, by
angulation of the probe, and sometimes through the open
sagittal suture. Both thalami are found in close apposition.
The third ventricle may be observed in the midline with
the interventricular foramina of Monro; in a slightly
more posterior plane, the atrium of the lateral ventricle
with choroid plexus appears on each side. Close to the
cranial base and in the midline, the basal cistern contains
the blood vessels of the circle of Willis and the optic
chiasm. This plane also provides a full view of the Sylvian
fissures. Evaluation of this latter anatomic landmark is
of crucial importance; to image it, it is useful to indent,
gently but firmly, the anterior fontanelle, otherwise the
lateral shadowing from the parietal bones will impair
visualization of the insula and the Sylvian regions.
Transcerebellar plane (Figure 1d). The transcerebellar
plane is the only coronal plane that is obtained through the
posterior fontanelle. It enables visualization of the occipital
horns of the lateral ventricles and the interhemispheric
fissure. Depending upon gestational age, the calcarine fissure
(Figure 3) and, more deeply, the parieto-occipital fissure,
can also be seen. Both cerebellar hemispheres and the
vermis are also seen in this plane, in cross-section. The vermis
is more echogenic than are the cerebellar hemispheres.
Recommendations
- The midsagittal or median plane is the reference plane for assessing all major midline organs and their anomalies. In order to ensure adequate evaluation of supra- and infratentorial anatomy, this plane should be sought through the anterior or posterior fontanelle, or even the sagittal non-ossified suture, depending on the particular structure of interest. This is achieved by gentle manipulation of the fetal head into the desired position using the free hand (GOOD PRACTICE POINT).
Care should be taken in using corpus callosal biometry
to diagnose hypoplasia of the corpus callosum, since a
short, thin or thick corpus callosum is not necessarily
synonymous with abnormality of this anatomical
structure. For this reason, a qualitative assessment
is much more important than a quantitative one,
i.e. check that all four components of the corpus
callosum are visible and sonographically normal
(GOOD PRACTICE POINT).
Median or midsagittal anterior plane
(Figure 4a). The
midsagittal anterior plane is obtained through the anterior
fontanelle and enables good visualization of the cerebral
midline. When examining the infratentorial structures,
an approach through the posterior fontanelle is preferred
(see below). This median view shows the corpus callosum
with all its components. In particular, the four parts
of the corpus callosum – rostrum, genu, body and
splenium – and their strict relationship with the cavum
septi pellucidi and the cavum vergae,when present, should
be visualized. Below the cavum septi pellucidi, the third
ventricle can be identified as a hypoechoic structure, but
its cranial portion is hyperechogenic due to the presence
Figure 2 Transfrontal plane of fetal head. After 26 gestational
weeks, olfactory sulci (arrows) can be visualized just above
sphenoid bone.
of the tela choroidea. The infratentorial anatomy is also
visible in this plane, particularly the vermis and the fourth
ventricle. However, to display adequately and assess these
structures, it is recommended to use a posterior approach
(median or midsagittal posterior plane; see below). Using
color Doppler, the anterior cerebral artery, pericallosal
arteries with their branches and the vein of Galen may
be seen, but its role is marginal in the assessment of the
corpus callosum.
Median or midsagittal posterior plane (Figure 5). The
midsagittal posterior plane is obtained through the sagittal
suture or, better, the posterior fontanelle. Care should
be taken to avoid shadowing from the occipital bone
onto the posterior fossa and the cisterna magna, which
may limit, or make impossible, clinical interpretation of
the image. With this posterior approach, the cerebellar
vermis is insonated from above and the ultrasound beam
is at approximately 90◦ relative to the brainstem, creating
the best conditions for visualizing this part of the brain
which may be challenging to display on ultrasound. All
Figure 5 Midsagittal or median posterior plane is obtained by
indenting posterior fontanelle and is best for assessing posterior
fossa. Anatomical landmarks seen in this plane: cerebellar vermis
(V), with fastigium and fourth ventricle (arrow); cisterna magna
( ); tentorium (double arrow); brainstem (bs) with pons. Sylvian
aqueduct (arrowhead) may also be demonstrated.
the anatomical midline landmarks of the vermis and
the posterior fossa can be studied thoroughly using
this approach. These include: the median plane of the
entire vermis, with the fastigium, the primary fissure
(and also the secondary fissure, late in pregnancy) and
the vermian lobules; the triangular fourth ventricle; the
cisterna magna; the brainstem with the midbrain, pons
and medulla oblongata. The upper boundary of the
posterior fossa, represented by the tentorium, can also
be identified. On this median view, it is often possible to
visualize fluid in the Sylvian aqueduct, particularly during
the second trimester.
Parasagittal planes (Figure 4b). The parasagittal planes
are obtained by moving or tilting the transducer slightly
laterally from the midsagittal plane, to either side. They
depict the lateral ventricles, choroid plexuses, periventricular
brain parenchyma and, mainly in the third trimester,
the gyri of the cortex, on the convex surface of the
brain, as well as a variable portion of the insulae/Sylvian
fissures. A more lateral view will enable visualization of
the temporal horns of the ventricles and the insulae.
Additional planes. The planes described above represent
the key planes to be obtained and evaluated every
time a targeted fetal neurosonographic examination is
performed. However, according to the focus of the
examination, other intermediate sagittal and coronal
planes can be displayed and are sometimes very useful.
In particular, for example, for a thorough examination of
the posterior fossa, additional coronal planes focused on
the cross-section of the vermis may be required.
Fetal spine
Recommendation
The ability to visualize the conus medullaris lying on the
ventral border of the spinal canal, close to the vertebral
bodies, is a good hint to determine the normality of the
lumbosacral spine (GOOD PRACTICE POINT).
Three scanning planes can be used to evaluate the
integrity of the spine. The choice depends upon the fetal
position. Usually, only two of these scanning planes are
possible in any given case, but manipulation of the fetus or
three-dimensional (3D) ultrasound can be used to obtain
the third plane when needed.
Transverse or axial planes. In transverse or axial planes,
the examination of the spine is a dynamic process,
performed by sweeping the transducer along the entire
length of the spine, while remaining within the axial plane
of the level being examined (Figure 6). The vertebrae have
different anatomic configurations at different levels: fetal
thoracic and lumbar vertebrae have a triangular shape,
with the ossification centers surrounding the neural canal;
the cervical vertebrae are quadrangular in shape; and
sacral vertebrae are flat.
Sagittal planes. In sagittal planes, the ossification centers
of the vertebral body and posterior arches form two
parallel lines that converge in the sacrum. When the fetus
is prone, a true sagittal section can also be obtained,
Figure 6 Axial views of fetal spine at different levels: (a) cervical;
(b) thoracic; (c) lumbar; (d) sacral. Arrows indicate the three
ossification centers of a vertebra. Note intact skin overlying spine.
In (a–c), spinal cord is visible as hypoechoic ovoid with central
white dot (arrowhead).
by directing the ultrasound beam across the non-ossified
spinous process. This allows imaging of the spinal canal
and of the spinal cord within it (Figure 7). In the late
second and third trimesters, the conus medullaris is usually
found at the level of the second/third lumbar vertebrae
(L2–L3)19–21. Integrity of the neural canal is also inferred
from the regular disposition of the ossification centers of
the spine and the presence of soft tissue covering the spine.
If a true sagittal section can be obtained, visualizing the
conus medullaris in its normal location further strengthens
the diagnosis of normality (Figure 7).
Recommendation
The use of high-frequency transabdominal linear/ microconvex transducers enhances the assessment of the spinal cord and conus medullaris in the midsagittal view of the spine (GOOD PRACTICE POINT).
Three-dimensional ultrasound
Recommendation
The use of a 3D ultrasound approach is recommended
in targeted neurosonography, particularly when a
good two-dimensional image is difficult to obtain, in
order to benefit from both the enhanced resolution and the possibility of performing multiplanar imaging
correlation (GOOD PRACTICE POINT).
While there are some useful landmarks ensuring
adequacy of a midsagittal/median plane of the fetal brain
(e.g. corpus callosum and vermis), it is not uncommon
for minor deviation from the perfect midsagittal view to
go unnoticed by the operator. This, in turn, may affect
not only measurements but also qualitative assessment
of the brain and brainstem. The employment of 3D
ultrasound for targeted neurosonography may, therefore,
Figure 7 Sagittal view of fetal spine. Using unossified spinous
process of vertebrae as acoustic window, contents of neural canal
are demonstrated. After 20weeks, conus medullaris (arrow) is
normally positioned at level of second/third lumbar vertebrae
(L2–L3), leaving, dorsally, triangular zone filled with cerebrospinal
fluid. Note continuity of skin (arrowheads).
Figure 8 Coronal view of fetal spine (arrows). This plane is useful
to rule out hemivertebrae and diastematomyelia. It can be obtained
at level of vertebral bodies (a) or, more posteriorly, at level of
arches (b). Objective is to rule out abnormal angling of spine.
be particularly useful, contributing in two main ways. First, by using multiplanar image correlation, it is possible to obtain perfectly aligned views on the three orthogonal planes (Figure 9); second, the possibility of displaying thicker ‘slices’ of the brain increases the signal-to-background noise ratio on all three planes, with significant enhancement of image quality. These advantages support our recommendation to use a 3D approach to neurosonography7,22,23. In addition, assessment of the fetal spine benefits from 3D rendering and reconstruction of the coronal planes at the level of the vertebral bodies and/or posterior arches24 (Figure 10).
Neurosonography at 13–17 gestational weeks
Introduction into clinical practice of high-frequency transducers25–28 and the increasing trend to perform
an anatomic evaluation earlier in gestation, also recommended
by ISUOG, amongst others29–31, have led to early
referrals for suspicion of brain or spinal malformations.
However, the advanced assessment of the fetal brain at
13–14 gestational weeks differs somewhat from that at
15–17weeks, owing to the rapid changes that the fetal
CNS undergoes around these gestational ages.
The recommended approach is to use transvaginal
ultrasound. Although the newer high-frequency
transabdominal transducers allow an adequate early
neurosonographic examination, especially if the maternal
body mass index is ≤25 kg/m2 and the focus of the examination
is not the posterior fossa, use of higher-frequency
transvaginal transducers (6–12 MHz) leads to significant
enhancement in the display of early fetal cerebral anatomy
and allows more thorough assessment of this anatomic
region. The approach of choice at 13–14 weeks of
gestation includes assessment of the axial transventricular
(Figure 11a) and transthalamic (Figure 11b) planes,
in association with the midsagittal plane (Figure 11c)
reconstructed from 3D volume datasets that are acquired,
unlike in later gestation, from an axial view of the fetal
head. This is possible due to the significantly lower degree
of ossification of the fetal skull at this early gestational
age. This, combined with the use of multiplanar imaging,
leads to perfect midsagittal and coronal images of
the ventricular system and the whole brain, although
attention at this gestational age is often focused mainly
on the diencephalon and posterior fossa (Figure 11c,d)31.
The need to assess the axial planes is related to the
mounting body of evidence supporting the early diagnosis
of open spina bifida32,33. All sonographic signs described
are due to the leakage of cerebrospinal fluid through the
open dysraphism. The key views to detect these signs
are the transventricular plane34,35 (Figure 11a) and the
posterior midsagittal one29,32 (Figure 11c). The latter
is also the reference plane for the early assessment of
cystic vermian abnormalities31,36; such an assessment
has to be undertaken with great caution, particularly
when these abnormalities are apparently isolated, due to
the high risk of false-positive diagnoses37. Should there
be any suspicion of open spina bifida, direct evidence
of the malformation should then be obtained with a
high-resolution transvaginal assessment of the fetal spine.
At 15–17 gestationalweeks, the recommendation to use
the transvaginal approach remains, enabling evaluation
of structures not seen at earlier ages10,38,39. Preferred
acquisition planes are coronal and sagittal ones, due to the
position of the head facilitating a transfontanellar/sagittal
suture approach (Figure 12). The axial planes are
obtained either using the transabdominal approach, using
the transvaginal approach with manipulation of the fetal
head, or using 3D reconstructions.
Transventricular plane. At 13–14 gestational weeks,
the transventricular plane allows assessment of the
amount of cerebrospinal fluid around the choroid
plexuses, the midline and the thin layer of developing
brain parenchyma around the lateral ventricle
(Figure 11a). At 15–17 gestational weeks, more information
can be gathered about the brain parenchyma
and the ventricular system. It should also be underlined
that an oval anechogenic structure is often evident at
this gestational age, along the midline (Figure 12a). It
was demonstrated recently that this structure, formerly
thought to represent the third ventricle, is in fact the
cavum veli interpositi (Figure 12), and that it is rather
common, being visible in almost half of fetuses at
13–17 gestational weeks38.
Midsagittal/median view. At 13–14 gestational weeks,
the reconstructed midsagittal/median plane allows
complete assessment of the ventricular system, since the
aqueduct is much more prominent than it is later in gestation
(Figure 11c). In addition, this is the best approach
to assess the infratentorial anatomy in cases in which a
‘cystic posterior fossa’ (mostly a normal finding related
to the development of these structures) is detected at
nuchal translucency screening31. In some cases, starting
from 14–17 gestational weeks, the first evidence of the
cavum septi pellucidi38 and the anterior portions of the
corpus callosum can be visualized39 (Figure 12d). In the
posterior fossa, the anatomy of the developing cerebellar
vermis and the brainstem can be studied. The operator
should be aware of the fact that, at this gestational age, the
appearance of the cerebellum is completely different from
that which we are used to seeing during the 18–23-week
examination. An example is the fourth ventricle, which is
continuous, initially, with the Blake’s pouch, and, when
the Blake’s pouch ruptures to create the Magendie foramen,
with the cisterna magna (Figures 11 and 12)40,41.
Even though the potential of the early anatomical
assessment has increased considerably, for most
CNS abnormalities, a follow-up neurosonographic
examination after 20weeks of gestation is warranted. Significant exceptions, with straightforward diagnosis and no need for a follow-up scan, are the lethal or near-lethal anomalies, such as exencephaly-anencephaly, gross cephalocele and holoprosencephaly.
FETAL BRAIN MRI
Recommendation
Fetal brain magnetic resonance imaging (MRI) is
considered complementary to neurosonography; it can
add significant clinical information when requested to
answer specific questions posed by the neurosonologist
that the targeted fetal CNS evaluation could not answer.
When neurosonographic evaluation is unavailable or
the level of performance inadequate, it can replace
neurosonography as the second-line evaluation, as long
as the operator has sufficient training in fetal brainMRI
(GOOD PRACTICE POINT).
ISUOG guidelines for the performance and reporting
of fetal MRI are available and provide useful information
on this technique42. It should be underlined that, when
the indication for this complementary imaging modality
is appropriate, and the diagnostic query specified clearly,
MRI may contribute significantly to the final diagnosis.
However, MRI should be performed only after, and to
complement, a neurosonographic examination, if this
is considered to be indicated by the trained operator in
order to address a relevant diagnostic or clinical query.
Published evidence indicates that, when an adequate
neurosonographic examination is carried out by an
experienced operator, according to the criteria specified
in this Guideline, a MRI examination is required in
only 7–15% of cases43–45. It is important, both for the
sake of the patient and to avoid inappropriate referral,
not to rush from suspicion of CNS malformation on
screening ultrasound, or on suboptimal neurosonography
not meeting the technical criteria described herein, to
MRI42,46.
GUIDELINE AUTHORS
This Guideline was produced on behalf of the International
Society of Ultrasound in Obstetrics and Gynecology
(ISUOG) by the following authors, and peer reviewed by
the Clinical Standards Committee.
D. Paladini, Fetal Medicine and Surgery Unit, Istituto G.
Gaslini, Genoa, Italy
G. Malinger, Division of Ultrasound in Obstetrics and
Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky
Medical Centre, Sackler School of Medicine, Tel Aviv
University, Tel Aviv, Israel
R. Birnbaum, Division of Ultrasound in Obstetrics and
Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky
Medical Centre, Sackler School of Medicine, Tel Aviv
University, Tel Aviv, Israel
A. Monteagudo, Carnegie Imaging for Women, Obstetrics,
Gynecology and Reproductive Science, Icahn School
of Medicine at Mount Sinai, New York, NY, USA
G. Pilu, Obstetric Unit, Department of Medical and
Surgical Sciences, University of Bologna, Bologna, Italy
L. J. Salomon, Hˆ opital Necker Enfants Malades, AP-HP,
and LUMIERE platform, EA 7328 Universit e de Paris,
Paris, France
I. E. Timor-Tritsch, Division of Obstetrical and Gynecological
Ultrasound, NYU School of Medicine, New York,
NY, USA
CITATION
This Guideline should be cited as: ‘Paladini D, MalingerG, Birnbaum R, Monteagudo A, Pilu G, Salomon LJ, Timor-Tritsch IE. ISUOG Practice Guidelines (updated): sonographic examination of the fetal central nervous system. Part 2: performance of targeted neurosonography. Ultrasound Obstet Gynecol 2021. https://doi.org/10.1002/uog.23616.
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APPENDIX 1 Grades of recommendation and levels of evidence used in ISUOG Guidelines
Classification of evidence levels
1++ | High-quality meta-analyses, systematic reviews of randomized controlled trials or randomized controlled trials with very low risk of bias |
1+ | Well-conducted meta-analyses, systematic reviews of randomized controlled trials or randomized controlled trials with low risk of bias |
1- | Meta-analyses, systematic reviews of randomized controlled trials or randomized controlled trials with high risk of bias |
2++ | High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with very low risk of confounding, bias or chance and high probability that the relationship is causal |
2+ | Well-conducted case–control or cohort studies with low risk of confounding, bias or chance and moderate probability that the relationship is causal |
2- | Case–control or cohort studies with high risk of confounding, bias or chance and significant risk that the relationship is not causal |
3 | Non-analytical studies, e.g. case reports, case series |
4 | Expert opinion |
Grades of recommendation
A | At least one meta-analysis, systematic review or randomized controlled trial rated as 1++ and applicable directly to the target population; or a systematic review of randomized controlled trials or a body of evidence consisting principally of studies rated as 1+ applicable directly to the target population and demonstrating overall consistency of results |
B | Body of evidence including studies rated as 2++ applicable directly to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+ |
C | Body of evidence including studies rated as 2+ applicable directly to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++ |
D | Evidence level 3 or 4; or evidence extrapolated from studies rated as 2+ |
Good practice point | Recommended best practice based on the clinical experience of the guideline development group |