Download TurningPoint 2008

The prevalence and risk of Down
Syndrome in monozygotic and
dizygotic multiple pregnancies in
Europe: implications for prenatal
screening
B. Boyle, J.K. Morris, R. McConkey, E. Garne
M. Loane, MC. Addor, M. Gatt, M. Haeusler,
A. Latos-Bielenska, N. Lelong, R. McDonnell1,
C. Mullaney, M. O’Mahony and H Dolk.
Background
Both dizygotic twinning and Down Syndrome are
associated with older maternal age
Prenatal screening uses maternal age, along with
ultrasonic and biochemical tests to estimate risk
of Down syndrome and so aid the decision to
proceed to more invasive tests
Lack of precise age specific risks in multiple
pregnancies may potentially lead to inaccurate
estimates of risk of Down Syndrome
The rate of fetal loss after amniocentesis is twice
as high in multiple as in singleton pregnancies
Technically more difficult to carry out an
amniocentesis on a multiple pregnancy
Epidemiological Literature
comparing risk of Down Syndrome
in multiple compared to singleton
pregnancies: per baby, analysis
carried out on live births
Author
Measures of
association
Type of multiple
birth
Number of DS cases
from multiple births
Estimate (95% CI)
Adjusted for
maternal age
Hay 1970
Odds Ratio
Unlike sex
23
0.81
no
Odds Ratio
Like sex
33
0.56
no
Kallen 1986*
Relative Risk
All twins
10
0.60 (0.32-1.11)
no
Doyle 1970
Relative Risk
All twins
42
0.68 (0.49-0.92)
Yes
Tang 2006
Relative Risk
All Twins
38
0.95 (0.83-1.06)
Yea
Kallen included stillbirths
Conflicting advice available for prenatal screening
Risk per fetus
Similar, but in monozygotic pregnancy both fetuses will
be affected
Gonce (2005), Sebire (2006)
Risk per pregnancy
Similar as the risk per fetus is lower
Wald (2005) Cuckle (1998)
UK (NICE) guidelines
Risk per pregnancy is higher, but they do not state by
how much
French guidelines
Use singleton risk estimates, but do not state if this is per
fetus or per pregnancy
Aim of the Study
To calculate, using a large European birth
population, the maternal age-specific prevalence
of DS in monozygotic and in dizygotic
pregnancies and to explore the risk for each
relative to singleton pregnancies
Methods
Data from 10 EUROCAT congenital anomaly registries in 8 countries,
including the National Down Syndrome Cytogenetic Register, a UK
based registry affiliated to EUROCAT which provided case data
especially for this study
The total study population was 14, 849,746 births between 1990 and
2009, of which 2.89% were from multiple births.
EUROCAT DQI used to select registries with good ascertainment of
Down Syndrome
Included all livebirths, stillbirths and terminations for fetal anomaly
(TOPFA)
Methods
Correction factor was used to correct TOPFA cases for probability of survival to
20 weeks
Cases from like sex concordant pairs were considered to be monozygotic (3
unlike sex concordant pairs)
Denominators were available by maternal age, multiple birth and like and unlike
sex status
Weinberg’s rule: total twin pairs – 2(unlike sex pairs) = monozygotic twins was
used to estimate zygosity by maternal age in the population
Statistical methods: Poisson regression adjusting for country and maternal age
where appropriate
Proportion of mothers 35 years and over by
country 1990-2007/9
0.3
0.25
0.2
Percent 0.15
singleton births
Multiple births
0.1
0.05
0
Country
Prevalence per 10,000 births of DS cases from singleton and multiple
pregnancies, 1990-1999 and 2000-2009 by 5 years of maternal age for
England and Wales and for the rest of Europe separately
Rest of Europe
England and Wales
200
200
180
180
160
160
140
140
120
120
per
10,000 100
births
80
singletons 1990
100
sinletons 2000
80
60
60
40
40
20
20
0
multiples 1990
multiples 2000
0
<20
20-24
25-29 30-34
Maternal age
35-39
40-44
<20
20-24
25-29 30-34
Maternal age
35-39
40-44
Main findings per fetus
The risk of Down Syndrome for a fetus from any
multiple birth relative to a singleton birth when
adjusted for country and maternal age was:
0.58 (95%CI 0.53-0.62).
Only one fetus of a mother aged over 44 years
was diagnosed with Down Syndrome. The
expected number was 55.
Risk of Down Syndrome, per pregnancy, for monozygotic
and dyzygotic pregnancies relative to singleton pregnancies,
corrected for survival to 20 weeks’ gestation, by maternal age
Monozygotic twin
pregnancies
Dizygotic twin
pregnancies
2.5
2.5
2
2
1.5
Risk
relative
to singleton
pregnancy
1
1.5
Risk
relative
to singleton
pregnancy
1
0.5
0.5
0
<20
20-24 24-29 30-34 35-39 40-45
maternal age
0
20-24
24-29
30-34
35-39
maternal age
40-45
Main findings per pregnancy
The risk of Down Syndrome for a monozygotic pregnancy
relative to a singleton pregnancy when adjusted for
country and maternal age was:
0.34 (95% CI 0.25 – 0.44)
Both fetuses will be affected
The risk of Down Syndrome for a dizygotic pregnancy relative
to a singleton pregnancy when adjusted for country and
maternal age was:
1.34 (95%CI 1.23 – 1.46)
If the risk per fetus was the same as for a singleton pregnancy
this risk would be 2 as each fetus has an independent risk
of Down Syndrome
Discussion
Twin, and mainly monochorionic pregnancies are more fragile than singleton
pregnancies. When combined with a embryo / fetus with Down Syndrome
losses in pregnancy increase.
Prenatal screening and TOPFA are less common for Down Syndrome cases
from multiple pregnancies than for singletons at similar maternal ages
Assisted reproductive therapies:
With frozen embryos the egg was harvested from the mother or from a
donor at an age which is less than that of the mother at the index
pregnancy
Embryos with Down Syndrome, even when there is not pre-implantation
diagnosis may be more fragile than other embryos and therefore are not
selected for implantation
Conclusions
Fetuses from twin and higher order multiple
pregnancies in mothers who are over the age of
44 are very unlikely to be diagnosed as Down
Syndrome
The risk of Down syndrome per fetus is lower in
multiple than in singleton pregnancies at all
maternal ages
The risk of Down Syndrome in monozygotic and
dizygotic relative to singleton pregnancies
described here should be considered in both
genetic counselling and prenatal diagnosis
Acknowledgements:
Co-authors: B. Boyle, J.K. Morris, R. McConkey, E. Garne M.
Loane, MC. Addor, M. Gatt, M. Haeusler, A. LatosBielenska, N. Lelong, R. McDonnell1, C. Mullaney, M.
O’Mahony and H Dolk.
B Boyle was funded through a Northern Ireland Research
and Development Studentship through the Northern
Ireland Public Health Agency.
. EUROCAT is co‐funded by the EC, under the framework of
the EU Health Programme 2008‐2013, Grant Agreement
2010 22 04 (Executive Agency for Health & Consumers).
Boyle B, Morris J, McConkey R, Garne E,
Loane M, Addor M-C, Gatt M, Haeusler M,
Latos- Bielenska A, Lelong N, McDonnell R,
Mullaney C, O'Mahony M and Dolk H
Prevalence and risk of Down syndrome in
monozygotic and dizygotic multiple
pregnancies in Europe: implications for
prenatal screening.
British Journal of Obstetrics and Gynaecology.
121(7):809-19; discussion 820, 2014 Jun.