MATERNAL FETAL MEDICINE

Evolution of Down Syndrome Prenatal

bec
Screening Clinical Practices in Que
Audrée Gareau-Léonard, BSc;1 Alexandre Fillion;1,2 Laurence Labine, MD;1
Cédric Gasse, MD, MSc;1,2 Suzanne Demers, MD, MSc;1,3
Emmanuel Bujold, MD, MSc1,3
1

bec − Universite
Reproduction, Mother and Child Health Unit, CHU de Que
Laval Research Centre, Universite

Laval,

bec, QC
Que
2

Laval, Que
Department of Social and Preventive Medicine, Universite
bec, QC
3

Laval, Que
Department of Gynecology, Obstetrics and Reproduction, Faculty of Medicine, Universite
bec, QC

onard
A. Gareau-Le

Abstract Résumé

Objective: Prenatal screening for Down syndrome (DS) has evolved Objectif : Le de
pistage pre
natal de la trisomie 21 a grandement e
volue


greatly over the last decades with the improvement of first- and au cours des dernie res de

cennies en raison de l’ame
lioration du
second-trimester serum screening and the introduction of cell-free de
pistage des marqueurs se
riques aux premier et deuxie me trimestres
fetal DNA. This study aimed to estimate the impact of such changes
e du de
et de l’arrive
pistage de l’ADN fœtal acellulaire. Cette e
tude
on practices. e
visait a
valuer l’incidence de ces changements dans les pratiques.

Methods: This retrospective cohort study included fetuses and Méthodologie : Cette e
tude de cohorte re
trospective comporte des
newborns diagnosed with DS between 2005-2007 and 2015-2017 fœtus et nouveau-ne
s ayant reçu un diagnostic de trisomie 21 au

bec City. Data were
in the single obstetrical care centre in Que cours des pe
riodes de 2005 a  2007 et de 2015 a  2017 dans le centre
collected on the prenatal screening method, diagnosis, and de soins obste
tricaux de Que
bec. Des donne
es ont e

te

recueillies sur
delivery. The median was compared between the study periods.
thode de de
la me
pistage pre

natal, le diagnostic et l’accouchement.
La me
diane a e

te
compare
e entre les deux pe
riodes a
 l’e

tude.
Results: Complete clinical data were available for only 78 (66%) of 119
cases of DS. Significant changes were observed in screening Résultats : Les donne
es cliniques comple  tes e

taient disponibles pour
methods, including an increase in the use of first-trimester serum, seulement 78 (66 %) des 119 cas de trisomie 21. Des changements
ultrasound, and cell-free fetal DNA. No significant changes were noted significatifs ont e
te

observe
s par rapport aux me
thodes de de
pistage,
in terms of gestational age at diagnosis (median [interquartile range; notamment une augmentation du recours au de
pistage des
IQR]: 17.0 [16.0−20.9] weeks in 2005-2007 vs. 17.9 [16.3−22.5] marqueurs se
riques, au de
pistage e

chographique et au de
pistage de
weeks in 2015-2017; P = 0.49) and delivery or termination of l’ADN fœtal acellulaire au premier trimestre. Aucun changement
pregnancy (median 20.9 [IQR 18.0−23.3] weeks in 2005-2007 vs.
te
significatif n’a e
constate
en matiere d’a^ge gestationnel lors du
21.3 [18.4−23.4] weeks in 2015-2017; P = 0.46). The methods of diagnostic (me
diane [intervalle interquartile; IIQ] : 17,0 semaines
diagnosis did not change significantly over the decade, with [16,0−20,9 semaines] en 2005-2007, par rapport a  17,9 semaines
amniocentesis used 85% and 79% of the time, respectively (P = 0.19). [16,3−22,5 semaines] en 2015-2017; P = 0,49) et lors de
l’accouchement ou de l’interruption de grossesse (me
diane : 20,9
Conclusion: The increased use of first-trimester screening and cell- semaines [IQR 18,0−23,3 semaines] en 2005-2007, par rapport a 
free fetal DNA tests was not associated with earlier diagnosis of DS 21,3 semaines [18,4−23,4 semaines] en 2015-2017; P = 0,46). Les
or earlier delivery or termination of pregnancy. The use of chorionic me
thodes de diagnostic n’ont pas conside
rablement change
au
villus sampling should be encouraged for DS diagnosis when cours de ces 10 anne
es; en effet, le recours a  l’amniocente  se se
indicated because it could reduce the gestational age at diagnosis faisait respectivement dans 85 % et 79 % des cas (P = 0,19).
and termination if requested.
Conclusion : L’augmentation du recours aux de
pistages au premier
trimestre et de l’ADN fœtal acellulaire n’est pas lie
e au devancement
Key Words: pregnancy outcome; trisomy; Down syndrome;
du diagnostic de la trisomie 21, de l’accouchement, ni de l’interruption
prenatal diagnosis
de grossesse. Il y a lieu d’encourager le recours au pre
le
vement de
Corresponding author: Dr. Emmanuel Bujold, Reproduction, Mother
s choriales dans le diagnostic de la trisomie 21 lorsqu’il est
villosite
and Child Health Unit, CHU de Que
bec - Universite

Laval Research indique
, car il peut devancer l’a
^ ge gestationnel au moment du

Laval; Department of Gynecology, Obstetrics
Centre, Universite diagnostic et de l’interruption de grossesse si l’on en fait la demande.

Laval, Que
and Reproduction, Faculty of Medicine, Universite
bec
City, QC. emmanuel.bujold@crchudequebec.ulaval.ca
© 2019 The Society of Obstetricians and Gynaecologists of Canada/La
Competing Interests: See Acknowledgements. Société des obstétriciens et gynécologues du Canada. Published by
The authors have indicated that they meet the journal’s Elsevier Inc. All rights reserved.
requirements for authorship.
Received on July 25, 2019 J Obstet Gynaecol Can 2019;000(000):1−7
Accepted on September 26, 2019 https://doi.org/10.1016/j.jogc.2019.09.025

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MATERNAL FETAL MEDICINE
INTRODUCTION
own syndrome (DS), or trisomy 21, is one of the
D most common viable chromosomal disorders1 and
a major cause of intellectual and physical disabilities.2,3
Non-invasive screening for DS relies on maternal charac-
teristics,4−9 serum and ultrasound biomarkers,3,4 and ultra-
sound examination of the fetus in the first and second
trimesters.3,7 These methods can be combined in various
ways to give a risk assessment of DS.3,4 Cell-free fetal
DNA in maternal serum is now included in the screening
methods for fetal chromosomal anomalies.10 Currently,
women with positive screening test results are offered cho-
rionic villus sampling or amniocentesis for karyotyping
and diagnosis of chromosomal anomalies. Both methods
are invasive and associated with complications and risks,
including pregnancy loss.11 A high proportion (67% to
92%) of women whose fetuses are diagnosed with DS will
undergo medical termination of pregnancy.9,12−14 How-
ever, decisions regarding pregnancy termination are better
dealt with (physically and psychologically) when they occur
earlier in the pregnancy course.14−16 Efforts have been
made in the past years to allow the screening and diagnosis
in the first trimester of pregnancy. In the province of
Qu
ebec, the Trisomy 21 Prenatal Screening Program has
been offered to all women on a voluntary basis since 2010,
excluding women with multiple gestations. This screening
test provides a risk assessment of having a fetus with DS
on the basis of the mother’s age and two blood tests—one
in the first trimester to measure the biomarker pregnancy-
associated plasma protein A, and one in the second trimes-
ter to measure the concentrations of total human chorionic
gonadotropin, alpha fetoprotein, unconjugated estriol, and
inhibin A. A measure of the nuchal translucency can be
incorporated into the calculation.17
Even though the literature is abundant concerning the pre-
dictive value of DS screening, data on outcomes and clini-
cal practices in Qu
ebec and Canada are lacking. We aimed
to explore the impact of the screening method used on the
gestational age at the time of diagnosis and on the gesta-
tional age at delivery. Our second objective was to explore
the impact of screening method variations in the only
obstetrical centre in Qu
ebec City.
MATERIAL AND METHODS
We conducted a retrospective cohort study of pregnant
women whose fetuses or babies had a diagnosis of DS at
the CHU de Qu
ebec − Universit
e Laval, an academic hos-
pital centre in Qu
ebec City, Qu
ebec, between March 2005
to April 2007 and March 2015 to April 2017. This study
2  000 JOGC 000 2019
was approved by the Ethics Committee of the CHU de
Qu
ebec − Universit
e Laval.
We selected the participants from the hospital database by
using International Statistical Classification of Diseases and
Related Health Problems (ICD) codes (ICD-10 Q90, Q90.9,
O35.101, O35.103, O35.109; or ICD-9 655.11, 655.13,
758.0). We also had access to the internal database of the
genetics laboratory of the CHU de Qu
ebec − Universit
e
Laval for an exhaustive identification of all women who had
karyotyping carried out in the centre. All women whose fetus
had a diagnosis of DS detected by karyotyping from amniotic
fluid or chorionic villus analysis were eligible. Newborns
diagnosed after birth from blood karyotype were also eligible.
We collected data related to all types of screening methods
used for prenatal diagnosis of DS, along with gestational age
at the time of diagnosis and at delivery (termination or birth).
We computed medians and interquartile ranges of gestational
age at use of each screening method, at diagnosis, and at the
outcome (delivery, miscarriage, termination of pregnancy).
The evolution of the median gestational age at screening,
diagnosis, and outcome was compared using the Mann-
Whitney test. The trends in proportion were compared with
the chi-square test. All analyses were conducted using SPSS
25 statistical software (IBM Corp, Armonk, NY).
RESULTS
Out of 119 women, 78 (66%) had available data and
were included in our analyses (40 in 2005-2007 vs. 38 in
2015-2017). Forty-one were excluded due to incomplete
clinical information. The proportion of exclusion were
similar in both periods (30% vs. 39%). We observed no
difference in terms of median gestational age at termina-
tion of pregnancy between women included in and
excluded from (data available for 11 patients) the analyses
(21.0 vs. 20.7 weeks; P = 0.76). Other missing data came
from women who completed their pregnancy in another
centre. The median maternal age was similar in the study
periods (median 34 [interquartile range 29.3−38.8] years
in 2005-2007 vs. 33.5 [29.0−37.3] years in 2015-2017;
P = 0.88).
Table 1 shows that no significant change occurred in pre-
natal diagnosis between the two study periods and that
chorionic biopsies were observed in few cases in 2015-
2017; this method was not seen in 2005-2007. There were
three possible outcomes: delivery, miscarriage, and termi-
nation of pregnancy. In both periods, the majority of
women opted for termination of the pregnancy after
 Evolution of Down Syndrome Prenatal Screening Clinical Practices in Québec

Table 1. Evolution of the diagnosis of Down syndrome by study period

Period; median (interquartile range) or no. (%)
2005-2007 2015-2017
Diagnostic evolution (n = 40) (n = 38) P value
a
Median gestational age at diagnosis, wk 17.0 (16.0−20.9) 17.9 (16.3−22.5) 0.49
Moment of diagnosis 0.82
Prenatal diagnosis 34 (85) 33 (87)
Postnatal diagnosis 6 (15) 5 (13)
Method of diagnosis 0.19
Chorionic biopsy 0 3 (8)
Amniocentesis 34 (85) 30 (79)
Postnatal karyotyping 6 (15) 5 (13)
Pregnancy trimester at diagnosis 0.76
First trimester 1 (3) 3 (7.9)
Second trimester 32 (80) 29 (76.3)
Third trimester 1 (3) 1 (2.6)
Postnatal 6 (15) 5 (13)
Pregnancy outcome 0.48
Voluntary termination of pregnancy 30 (75) 25 (66)
Fetal miscarriage 1 (3) 3 (8)
Live birth 9 (23) 10 (26)
Median gestational age at the end of pregnancy, wk 20.9 (18.0−23.3) 21.3 (18.4−33.4) 0.46
a
Gestational age at delivery was used for cases diagnosed after birth.

diagnosis. We observed no significant difference between
study periods for the gestational age at diagnosis (Figure 1)
or for the gestational age at the end of the pregnancy
(Figure 2).
Conversely, we observed significant changes in the screen-
ing methods over time (Table 2). This can be explained by
the arrival of the Trisomy 21 Prenatal Screening Program
of Qu
ebec, which uses both first and second trimester
serum biomarkers to assess risk of DS. Nuchal translu-
cency measurement also significantly increased in the sec-
ond study period. Cell-free DNA was used in screening in
2015-2017 but not in 2005-2007. One patient underwent a
first-trimester cell-free DNA test that had a normal result.
In that particular case, the diagnosis of DS was made by
amniocentesis performed for fetal anomalies observed by
ultrasound at 20 weeks. Those changes in practice did not
improve the time of first positive screening (Figure 3).
Finally, the causes of postnatal diagnosis are reported in
Table 3.
DISCUSSION
We observed that first-trimester ultrasound and serum
screening along with first- and second-trimester cell-free
fetal DNA measurement were more commonly used in
2015-2017 when compared with 2005-2007. However, we
did not observe a significant change in terms of gestational
age at diagnosis or at delivery or termination of pregnancy.
The diagnosis and the decision regarding termination of
pregnancy continue to occur late in the second trimester of
pregnancy, even with the evolution of screening and diag-
nostic methods.
Offering earlier diagnosis and termination of pregnancy to
women is an important issue for many reasons. Decisions
regarding pregnancy termination are better dealt with
physically and psychologically when they occur earlier in the
pregnancy course.14−16 Women who undergo medical termi-
nation of pregnancy in the second trimester have a signifi-
cantly higher level of post-traumatic stress symptoms
6 weeks afterward compared with woman who have the
pregnancy terminated in the first trimester. Second trimester
abortion might be more difficult to deal with because
patients have already experienced fetal movements and may
have the opportunity to hold their baby and keep photo-
graphs after termination of pregnancy.15 Moreover, in the
first trimester, family and friends are not necessarily aware of
the pregnancy, thus affording the parents some privacy about
their decision.18 First-trimester terminations of pregnancy are

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MATERNAL FETAL MEDICINE
Figure 1. Gestational age at diagnosis.
also associated with fewer complications and risks than those
in the second trimester. Morbidity and mortality increase
with gestational age and abortion technique used.14,16
Several previous studies concluded that the majority (from
61% to 93%) of affected pregnancies with DS are usually
terminated.9,13,18,19 Our results demonstrate that although
new methods are available for the screening and diagnosis
of DS earlier in pregnancy, no significant changes were
observed during the decade for the time at screening, diag-
nosis, and termination of pregnancies. These results can be
explained by the fact that the public health insurance pro-
gram does not cover cell-free fetal DNA analysis or other
analysis performed in private clinics, and that policy conse-
quently reduces the number of screenings in the first tri-
mester (a conclusion that was also drawn in the study by
Weichert et al.9). In addition, the Trisomy 21 Prenatal
Screening Program of Qu
ebec provides a risk assessment
only in the second trimester, which precludes the choice of
earlier diagnosis and therefore an earlier termination of
pregnancy. Hume et al.20 observed that when they started
using first-trimester screening methods, particularly cell-
4  000 JOGC 000 2019
free fetal DNA, the gestational age at diagnosis and preg-
nancy termination decreased, mostly because first-trimester
screening allowed the use of chorionic villus sampling.
These investigators also concluded in their article that if
cell-free fetal DNA became a primary screening modality,
the gestational age at diagnosis could decrease even more.
Our study has some limitations. First, this was a retrospec-
tive study, and some data were not available because of
incomplete files. Second, we did not have access to all
results of the screening tests performed in private clinics
and the outcomes in some women who completed their
pregnancy outside Qu
ebec City. The proportion of missing
data in both study groups was similar, as was gestational
age at the end of pregnancy in the excluded and included
patients; this finding suggests that the missing data are less
likely to influence the results. Conversely, our observations
and the difficulties in obtaining optimal information on
prenatal screening and diagnosis emphasized the need for
better data collection of prenatal screening and diagnosis
locally, as well as at the provincial and national level. Third,
the data obtained were from one of the genetic centres
 Evolution of Down Syndrome Prenatal Screening Clinical Practices in Québec

Figure 2. Gestational age at the end of pregnancy.

Table 2. Evolution of screening methods by study period

Period; median (interquartile range) or no. (%)
2005-2007 2015-2017
Screening methods (n = 40) (n = 38) P value
Serum biomarkers <0.001
First trimester only 3 (8) 2 (5)
Second trimester only 17 (43) 2 (5)
First and second trimesters 0 18 (47)
Nuchal translucency 8 (20) 17 (45) 0.019
Value, mm 3.4 (2.3−5.6) 2.5 (1.9−4.7) 0.34
Ultrasound 0.079
First trimester only 3 (8) 7 (18)
Second trimester only 22 (55) 15 (40)
First and second trimesters 5 (13) 11 (29)
Cell-free fetal DNA <0.001
First trimester 0 7 (19)
Second trimester 0 5 (14)
Moment of first positive screening 0.072
First trimester 5 (13) 15 (40)
Second trimester 23 (58) 16 (42)
Third trimester 1 (3) 3 (8)
Postnatal 2 (5) 3 (8)
Median gestational age, wk 16 (14.4−20.6) 15 (12.7−19.8) 0.353
Screening based on maternal age only 9 (23) 1 (3) 0.009

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MATERNAL FETAL MEDICINE

Figure 3. Gestational age at first positive screening.

Table 3. Reasons for postnatal diagnosis by study period

Period; no. (%)
2005-2007 2015-2017
Reasons (n = 6) (n = 5)
Refusal of screening — 1 (20)
Refusal of diagnostic procedure 1 (17) 0
Failure of screening methods
Serum biomarkers first trimester only — —
Serum biomarkers first trimester with nuchal translucency — 1 (20)
Serum biomarkers second trimester only 1 (17) —
Serum biomarkers second trimester with nuchal translucency 4 (67) —
Combined serum biomarkers in the first and second trimester only — —
Combined serum biomarkers in the first and second trimesters with nuchal translucency — 2 (40)
Patients not eligible for free provincial screening (i.e., multiple pregnancy) — 2 (40)

located in Qu
ebec, namely the one for the east side of the
province, which is located in Qu
ebec City. To have a com-
plete portrait of the trends in genetic screening and diagno-
sis of autosomal aneuploidy in Qu
ebec, other centres in
this province should be consulted.
CONCLUSION
We believe that the following recommendations should be
considered: (1) screening and diagnosis in the first trimester
should be prioritized to avoid unnecessary risks for pregnant

6  000 JOGC 000 2019

 Evolution of Down Syndrome Prenatal Screening Clinical Practices in Québec
women and allow them to make an earlier decision regard-
ing their pregnancy; (2) even though cell-free fetal DNA
testing has a high rate of detection and a low false-negative
rate, complementary non-invasive screening tests (e.g., ultra-
sound, blood tests) should be performed to ensure that the
right prognosis is made and to diagnose other pregnancy
complications (e.g., fetal malformation, abnormal placenta-
tion); (3) chorionic villus sampling should be done when
first-trimester screening results are positive because it could
allow earlier diagnosis; and (4) data collection and follow-up
should be improved to provide a better overview of the
landscape of the current use of prenatal screening and diag-
nosis across the province of Qu
ebec.
Acknowledgements
This study was funded by the Jeanne-et-Jean-Louis-
L
evesque Perinatal Research Chair at Universit
e Laval. Dr.
Bujold holds a salary award from the Fonds de Recherche
du Qu
ebec-Sant
e. All authors declare that they have no
competing interests. We thank Prof. Jean Gekas for provid-
ing the access to the CHU de Qu
ebec karyotype database.
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