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. McDonnell 1 , 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 Hay 1970 Kallen 1986* Doyle 1970 Tang 2006

Odds Ratio Odds Ratio Relative Risk Relative Risk Relative Risk

Type of multiple birth

Unlike sex Like sex All twins All twins All Twins

Number of DS cases from multiple births Estimate (95% CI) Adjusted for maternal age

23 33 10 42 38 0.81

0.56

0.60 (0.32-1.11) 0.68 (0.49-0.92) 0.95 (0.83-1.06) no no no Yes 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

0,3

Proportion of mothers 35 years and over by country 1990-2007/9

0,25 0,2

Percent

0,15 0,1 0,05 0 singleton births Multiple births

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

200 180 160 140 120

per 10,000 births

100 80 60 40 20 0

England and Wales

<20 20-24 25-29 30-34

Maternal age

35-39 40-44

Rest of Europe

200 180 160 140 120 100 80 60 40 20 0 <20 20-24 25-29 30-34

Maternal age

35-39 40-44 singletons 1990 sinletons 2000 multiples 1990 multiples 2000

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

Risk relative to singleton pregnancy

1,5 1 0,5 0 <20 20-24 24-29 30-34

maternal age

35-39 40-45 2

Risk relative to singleton pregnancy

1,5 1 0,5 0 20-24 24-29 30-34

maternal age

35-39 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. Latos Bielenska, N. Lelong, R. McDonnell 1 , 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.