This Journal Club presentation provides a summary and discussion of the following free access article published in UOG: Neurodevelopmental outcome of fetuses with increased nuchal translucency and apparently normal prenatal and/or postnatal assessment: a systematic review A. Sotiriadis, S. Papatheodorou, G. Makrydimas Volume 39, Issue 1, Date: January 2012, pages 10–19. This can be accessed here: http://onlinelibrary.wiley.com/doi/10.1002/uog.10143/abstract

1. UOG Journal Club: January 2012
Neurodevelopmental outcome of fetuses with increased nuchal
translucency and apparently normal prenatal and/or postnatal assessment:
a systematic review
A Sotiriadis, S Papatheodorou and G Makrydimas
Volume 39, Issue 1, Date: January 2012, pages 10–19
Journal Club slides prepared by Dr Aly Youssef
(UOG Editor for Trainees)

2. Background
• Increased nuchal translucency (NT) is associated with an
increased risk for various adverse pregnancy outcome including:
- chromosomal abnormalities
- genetic syndromes
- structural abnormalities (mainly congenital heart defects)
- intrauterine infection and fetal demise
• However, little is known about the long-term neurodevelopmental
outcome of children with increased NT and normal karyotype that
were apparently healthy at birth.

3. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Objective: To systematically review evidence on the
neurodevelopmental outcome of fetuses with increased first
trimester NT and lack of chromosomal, structural or
recognizable genetic syndromes at birth

4. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Methods
The literature was systematically reviewed (up to September 2011) for studies
with 1st trimester NT measurement and postnatal follow-up
Study selection
• Cohort or case-control studies
• Provision of sufficient details in order to identify only cases with isolated increased
NT (i.e. without identifiable chromosomal abnormalities, syndromes or congenital
structural defects)
• No language restrictions
Cases in which increased NT was associated with chromosomal, genetic or
structural abnormalities were excluded

5. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Methods
The studies were grouped according to the cut-off
used for increased NT
>99th >95th
All centile centile > 3 mm
The rates of developmental delay were separately
calculated for
Children with ↑ NT, normal karyotype, normal Children with ↑ NT, normal karyotype and
2nd trimester anomaly scan and absence of normal 2nd trimester anomaly scan (i.e.
structural defects and identifiable before confirmation of normal anatomy at
syndromes after birth birth)
A secondary analysis was also attempted according to the presence of absence of nuchal
edema at the second trimester scan

6. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Results
337
studies
included
181 studies: excluded on title and abstract
156 studies
132 studies: excluded for lack of outcome data on
postnatal neurodevelopmental delay
7 studies: excluded for specifically assessing fetuses
with ↑ NT for a genetic syndrome
17 studies
included in the systematic review

7. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Fetuses with ↑ NT and normal at birth
NT Number Pooled rate of neurodevelopmental
cut-off of studies delay (N, 95% CI)
Total 17 1.14%
(28/2458, 0.79–1.64)
99th centile 8 0.96%
(15/1567, 0.58–1.58)
95th centile 4 1.05%
(7/669, 0.51–4.88)
3 mm 5 2.70%
(6/222, 1.24–5.77)

8. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Fetuses with ↑ NT and normal 2nd trimester anomaly scan
NT Number Pooled rate of neurodevelopmental
cut-off of studies delay (N, 95% CI)
99th centile 8 1.08%
(15/1666, 95% CI 0.76–1.56)
95th centile 4 1.01%
(7/691, 0.49–2.07)
3 mm 5 2.47%
(6/243, 1.14–5.28)

9. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Presence of nuchal edema at the second trimester scan (4 studies)
NT>99th centile Pooled rate of neurodevelopmental
AND delay (N, 95% CI)
Normal nuchal fold 0.66%
(10/1494, 0.36–1.21)
Persistent nuchal 1.06%
edema (1/94, 0.19–5.78)

10. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Discussion
• Neurodevelopmental delay in fetuses with ↑ NT, normal fetal
karyotype and lack of structural defects or identifiable syndromes is
about 1%
• Rates of neurodevelopmental delay reported for the general
population is approximately 3%
• The low rate for developmental delay did not differ across the
various subgroup analyses

11. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Limitations
• Absence of firm consensus on the definition of developmental
delay
• Possible sources of bias:
1. Screening bias: most studies used telephone interviews (parents may
under- or over-estimate child’s development)
2. Ascertainment bias: most studies did not offer sufficient information
about the steps which followed identification of high-risk infants at
screening
• Syndromes are not always reliably identified (5/28 cases had an
unidentified genetic syndrome)

12. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Conclusion
The risk for developmental delay in fetuses with increased first-
trimester NT is not increased compared to the general population,
after exclusion of chromosomal abnormalities, structural defects
and genetic syndromes.

13. Neurodevelopmental outcome of fetuses with increased nuchal translucency and
apparently normal prenatal and/or postnatal assessment: a systematic review
Sotiriadis et al., UOG 2012
Discussion points
• What advice is currently given in your unit to parents when a fetus with
nuchal translucency thickness of > 3mm (or > 95th centile) has a
normal karyotype and anomaly scan?
• What does this systematic review demonstrate about the neurological
outcome for such fetuses?
• Do we need to wait till after birth to be able to reassure the parents
about the outcome of pregnancy?
• What conditions need to be met for us to be able to say that there is no
increase in postnatal neurological deficit?
• What are the study limitations?