SMFM Fellowship Series Article

Number of Risk Factors in Down Syndrome

Pregnancies
Deana J. Hussamy, MD1 Christina L. Herrera, MD1 Diane M. Twickler, MD1,2 Donald D. Mcintire, PhD1
Jodi S. Dashe, MD1

1 Department of Obstetrics and Gynecology, University of Texas Address for correspondence Jodi S. Dashe, MD, Department of
Southwestern Medical Center and Parkland Hospital, Dallas, Texas Obstetrics and Gynecology, University of Texas Southwestern Medical
2 Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9032
Center and Parkland Hospital, Dallas, Texas (e-mail: Jodi.dashe@utsouthwestern.edu).

Am J Perinatol

Abstract Objective The objective of this study was to evaluate risk factor prevalence in
pregnancies with fetal Down syndrome, in an effort to characterize efficacy of
population-based screening.
Study Design Retrospective review of singleton pregnancies with delivery of live born

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or stillborn infant with Down syndrome from 2009 through 2015. Risk factor categories
included maternal age
35 years, abnormal serum screening, identification of
1
ultrasound marker at 16 to 22 weeks (nuchal thickness
6 mm, echogenic intracardiac
focus, echogenic bowel, renal pelvis dilatation, femur length <third percentile), and
detection of a major fetal anomaly. Statistical analyses included χ2 test and Mantel–
Haenszel χ2 test.
Results Down syndrome infants represented 1:428 singleton births. All risk cate-
gories were assessed in 125 pregnancies and included abnormal serum screen in 110
(88%),
1 ultrasound marker in 66 (53%), and
1 anomaly in 41 (34%). The calculated
risk was at least 1:270 in 93% of Down syndrome pregnancies. More pregnancies had
multiple risk factors than had a single risk factor, 90 (72%) versus 30 (24%), p < 0.001.
Keywords An abnormal ultrasound marker or anomaly was identified in >50% of fetuses in women
► Down syndrome <35 years and in >75% of those 35 years and older.
► ultrasound markers Conclusion In a population-based cohort, sensitivity of second-trimester Down
► serum aneuploidy syndrome screening was 93%, with multiple risk factors present in nearly three-fourths
screening of cases.

There are four categories of risk factors that affect fetal Down
syndrome risk: maternal age (a priori risk), an aneuploidy
screening test result, minor ultrasound markers, and major
structural fetal anomalies. Risk assessment begins with an
individual’s age-related aneuploidy risk, which is then mod-
ified by other factors. Screening tests incorporate maternal
age, and a minor ultrasound marker may further increase
this risk by a likelihood ratio.1 However, counseling becomes
more complex when more than one ultrasound marker is
identified or when a structural fetal anomaly is encountered,
as little data are available with which to estimate degree of
risk.2 Though each risk factor has been extensively studied,
the prevalence of single and multiple risk factors among
pregnancies with fetal Down syndrome has not been well
characterized.
The position of the American College of Obstetricians and
Gynecologists is that risk adjustment based on second-tri-
mester ultrasound markers should be limited to individuals

received Copyright © by Thieme Medical DOI https://doi.org/

February 21, 2018 Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0038-1666974.
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Down Syndrome Risk Factors Hussamy et al.
with expertise in this area, with the understanding that
ultrasound is most effective for Down syndrome detection
when combined with other modalities.3 It is estimated that
sonography may detect 50 to 60% of Down syndrome
fetuses.4 Data from the 1990s suggested that only 25 to
30% of affected pregnancies have a major anomaly that could
be identified sonographically in the second trimester.5 The
prevalence of detectable structural anomalies in fetuses with
Down syndrome, alone and in combination with other risk
factors, has not been established in a contemporary cohort.
Such information would be helpful for counseling pregnant
women about the limitations of the sonogram.
Our objective was to evaluate the prevalence of risk factors,
alone and in combination, in pregnancies with fetal Down
syndrome, in an effort to characterize the efficacy of popula-
tion-based screening and thereby improve counseling.
Materials and Methods
We conducted a retrospective cohort study of singleton
pregnancies with fetal Down syndrome that received pre-
natal care at our institution and delivered live born or still-
born neonates (>500 g) at our hospital from January 2009
through December 2015. Pregnancies were identified from
an obstetrical database that contains selected pregnancy
outcomes and neonatal outcomes for all deliveries at our
hospital, including a description of structural and karyotypic
abnormalities. Medical records were reviewed for each
affected pregnancy, including all sonographic images and
reports. We serve a nonreferred population. In addition, as
our patients rarely elect pregnancy termination for fetal
Down syndrome, we were able to study the natural history
of affected pregnancies.
During the study period, all pregnant women, regardless
of age, were offered standard obstetrical sonography at
18 to 20 weeks and quadruple marker aneuploidy screen-
ing between 150/7 and 206/7 weeks.3 Pregnancies in which
abnormalities were detected subsequently received addi-
tional imaging with targeted sonography or fetal echocar-
diography, as appropriate. All examinations were performed
within our sonography unit by registered diagnostic medical
sonographers and overread by faculty who specialize in
obstetrical sonography. First-trimester sonography and
cell-free DNA screening were not included in this analysis.
For study purposes, minor ultrasound markers included
nuchal skinfold thickness
6 mm, echogenic intracardiac
focus, echogenic bowel that was as bright as bone, renal
pelvis dilatation
4 mm, and femur length < third percen-
tile using the Hadlock nomogram.6 Ultrasound markers were
used to increase the calculated fetal Down syndrome risk
based on a published summary table.7 The absence of such
markers was not used to decrease the risk.
Genetic counseling was offered to all women whose fetal
Down syndrome risk was at least 1:270 in the second
trimester, based on maternal age, serum aneuploidy screen-
ing, minor ultrasound marker(s) identified between 16 and
22 weeks, and structural fetal abnormality on any sonogram.
Counseling reflected that the fetal aneuploidy risk differs
American Journal of Perinatology
according to the specific structural abnormality, but in the
vast majority of cases, women were counseled that the risk
was significantly increased.7
Genetic counseling was also offered to all women
age
35 years at delivery, regardless of other risk factors. Prenatal
diagnosis was specifically offered as part of counseling. In all
cases, counseling was performed by certified genetic coun-
selors or physicians.
We evaluated four risk factor categories: maternal
age
35 years at delivery, abnormal aneuploidy screening,
minor ultrasound marker(s), and sonographic identification of
a major anomaly. Not all women elected serum aneuploidy
screening, and some women presented for care beyond
22 weeks. Our analysis focused on women who received serum
screening and sonography prior to 22 weeks, so that we could
evaluate the presence or absence of every risk factor category
in each pregnancy, separately and in combination. Major
anomalies included any structural abnormality that was
potentially life-threatening or likely to require surgical correc-
tion. For study purposes, cases of cystic hygroma, clinically
significant effusions, and mild ventriculomegaly were consid-
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ered major anomalies as has been done by other investigators.5
Statistical analyses included Pearson’s χ2 test and Mantel–
Haenszel’s χ2 test for trend. The p-values of < 0.05 were
judged statistically significant. Our study was approved by
the Institutional Review Board of the University of Texas
Southwestern Medical Center.
Results
During the 7-year study period, 185 women with singleton
pregnancies delivered live born or stillborn infants with
Down syndrome, representing 1:428 of the 79,154 singleton
deliveries at our hospital. Ten of these women did not receive
prenatal care in our system and 50 additional women did not
present early enough in gestation for aneuploidy screening,
or elected not to receive it, leaving 125 pregnancies for
analysis. There were 121 pregnancies with fetal trisomy
21, three with mosaicism for trisomy 21, and one with a
Robertsonian translocation, all confirmed with prenatal or
postnatal karyotype.
Demographic characteristics and pregnancy outcomes are
presented in ►Table 1. There were 10 stillborn infants (8%) and 1
neonatal death. For pregnancies with live born infants, the
median gestation age at delivery was 39 weeks. Fifty-two
(45%) were delivered by cesarean, with 12 (10%) performed
for nonreassuring fetal status. Twenty-one infants (17%) had
birth weights below the 10th percentile for gestational age.
Infant condition at birth was generally good; 95% had umbilical
artery pH >7.1 at delivery. Ultimately, 114 infants (91%) sur-
vived to hospital discharge. The neonatal death was secondary to
sepsis following perforation of a duodenal ulcer in an infant who
also had an endocardial cushion defect and was delivered at
31 weeks for nonreassuring fetal heart rate tracing.
At least one risk factor for Down syndrome was identified
in 120 pregnancies (96%), including 110 (88%) with abnormal
serum screening, 66 (53%) with one or more minor ultra-
sound markers, and 42 (34%) with identification of one or
 Down Syndrome Risk Factors Hussamy et al.

Table 1 Maternal, obstetrical, and neonatal characteristics

Characteristics N ¼ 125
Maternal age (y) 33.9  7.3
< 35 59 (47)

35 66 (53)
Race/ethnicity
Black 5 (4)
Hispanic 117 (94)
White 3 (2)
Parity
0 22 (18)
1 27 (22)

2 76 (61)
a Fig. 2 Number of risk factors identified in 125 pregnancies with fetal
Gestational age at delivery 39 (37, 39) Down syndrome.
< 37 wk 20 (17)
< 34 wk 5 (4)
single minor ultrasound marker which did not confer a
< 28 wk 0 (0) risk
1:270 when taken together with the serum screening

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Delivery by cesareana 52 (45) result, and one woman older than 35 years had a normal
Nonreassuring fetal status 12 (10) serum screening result and no abnormal sonographic find-
Infant birth weight (grams) 2,915  612 ings. Thus, 116 women (93%) with fetal Down syndrome
were identified to be at increased risk, of whom 18 (16%)
Small for gestational age 21 (17)
elected amniocentesis. The remaining 98 women received
Umbilical cord pH <7.1a 6 (5) formal genetic counseling about their increased risk and
Note: Data expressed as N (%), mean  SD, or median (Q1, Q3). declined amniocentesis or declined additional counseling
a
Data for live born infants (N ¼ 115). after being informed of their increased risk.
The number of risk factor categories in each Down syn-
more major structural abnormalities (►Fig. 1). In four of drome pregnancy is depicted in ►Fig. 2. Significantly, more
these pregnancies, the Down syndrome risk assessment did affected pregnancies had multiple risk factors than had a
not exceed the
1:270 threshold despite the presence of a single risk factor, 90 (72%) compared with 30 (24%),
risk factor: three women younger than 35 years had a p < 0.001. The various risk factor combinations diagnosed

Fig. 1 Risk factors identified in 125 pregnancies with fetal Down syndrome.

American Journal of Perinatology

Down Syndrome Risk Factors Hussamy et al.

Table 2 Risk factor categories in pregnancies with fetal Down Table 3 Risk factor categories in Down syndrome pregnancies,
syndrome stratified by maternal age at delivery

Pregnancies with Maternal age Maternal age p-Value

Down syndrome < 35 y
35 y
N ¼ 125 N ¼ 59 (47) N ¼ 66 (53)
No risk factor identified 5 (4) Number of additional risk factor categories
One risk factor category 30 (24) 0 5 (8) 1 (2) 0.004
Age 1 (1) 1 29 (49) 17 (26)
Serum 24 (19) 2 18 (31) 29 (44)
Marker(s) 5 (4) 3 7 (12) 19 (29)
Anomaly 0 Serum 47 (80) 63 (95) 0.01
Two risk factor categories 35 (28) Marker(s) 23 (39) 43 (65)
Age þ serum 15 (12) 1 19 (32) 30 (45) 0.004
Age þ marker(s) 2 (2) <1 4 (7) 13 (20) 0.26
Age þ anomaly 0 Anomaly 16 (27) 26 (39) 0.15
Serum þ marker(s) 9 (7) Note: Data expressed as N (%). Serum: Quadruple marker screening
Serum þ anomaly 7 (6) indicating second-trimester trisomy 21 risk  1:270 or term-pregnancy
trisomy 21 risk  1:365. Marker(s): One or more of the following

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Marker(s) þ anomaly
Three risk factor categories
Age þ serum þ marker(s)
Age þ serum þ anomaly
2 (2) ultrasound markers identified during sonography at 16 to 22 weeks:
36 (29) nuchal skinfold thickness
6 mm, echogenic intracardiac focus,
echogenic bowel as bright as bone, renal pelvis dilatation
4 mm,
22 (18) femur length < third percentile. Anomaly: One or more major struc-
7 (6) tural fetal abnormalities identified in the second or third trimester.

Age þ marker(s) þ anomaly 0

Serum þ marker(s) þ anomaly 7 (6)
Four risk factor categories 19 (15)
Note: Data expressed as N (%). Age: Maternal age
35 years at delivery.
Serum: Quadruple marker screening indicating second-trimester tris-
omy 21 risk
1:270. Marker(s): One or more of the following ultrasound
markers identified during sonography at 16 to 22 weeks: nuchal skinfold
thickness
6 mm, echogenic intracardiac focus, echogenic bowel as
bright as bone, renal pelvis dilatation
4 mm, femur length < third
percentile. Anomaly: One or more major structural fetal abnormalities
identified in the second or third trimester.
are presented in ►Table 2. Among Down syndrome preg-
nancies with a single risk factor, 80% had abnormal serum
screening. In just 4% of affected pregnancies were minor
ultrasound markers the only risk factor, and no woman
with fetal Down syndrome had a major fetal abnormality
as the only risk factor identified. Similarly, just one
woman
35 years had no other risk factor apart from her
age, such that 99% (65/66) of Down syndrome pregnancies in
women
age 35 years had a calculated risk that exceeded
the age related (or a priori risk). Furthermore, not only was
a minor ultrasound marker almost always associated with
another risk factor category but also 26% of those with
a minor ultrasound marker were found to have more than
one such marker. Twenty-eight per cent of affected pregnan-
cies occurred in women with two risk factor categories, 29%
with three, and 15% with all four risk factor categories.
As we found that 53% of infants with Down syndrome
were born to women 35 years and older, risk factor cate-
gories were further stratified by this cutoff. This is shown in
►Table 3. Women 35 years and older had significantly more
additional risk factors than younger women, p ¼ 0.004.
They were also more likely to have an abnormal serum
screening result, 95 versus 80%, p ¼ 0.01. Women
age
35 years were similarly more likely to have one or more
minor ultrasound marker identified, 65 versus 39%,
p ¼ 0.004. An ultrasound abnormality—major anomaly or
minor marker—was noted in 50 (76%) of pregnancies in
women
age 35 years with fetal Down syndrome, as
compared with 30 (51%) in those of younger women,
p ¼ 0.004.
With the understanding that virtually every pregnancy
receives second-trimester sonography, the role of abnormal
sonographic findings in Down syndrome detection was
further reviewed. During the study period, standard sono-
graphy was routinely performed in women 35 years and
older and in those with abnormal serum screening. Eighty
Down syndrome pregnancies (64%) were found to have one
or more minor ultrasound markers or a major structural
anomaly. As shown in ►Table 4, 34% of Down syndrome
fetuses had prenatally detected major anomalies. In 28
pregnancies (22%), a major anomaly was identified before
22 weeks, 10 (8%) later in the second trimester, and 4 (3%) in
the third trimester. Seven fetuses with Down syndrome had
an abnormality that resolved prior to delivery, including a
ventricular septal defect, ventriculomegaly, cystic hygroma,
or pericardial effusion. Neonatal structural abnormalities
were confirmed in 37% of live born infants with Down
syndrome, and the anomaly had been detected prenatally
in two-thirds of these cases. ►Table 4 lists the fetal anomalies
detected sonographically and also those who were not
identified until the neonatal period.

American Journal of Perinatology

 Down Syndrome Risk Factors Hussamy et al.

Table 4 Structural anomalies and prenatal anomaly detection in Down syndrome pregnancies

Fetuses with sonographic anomaly detected

All 42/125 (34)
Live birthsa 36/115 (31)
Stillbirths 6/10 (60)
b
Live born neonates with confirmed anomaly 43/115 (37)
Cardiac 32 (28)
Noncardiac 18 (16)
Live born neonate with anomaly detected prenatally 29/43 (67)
Major anomalies detected Endocardial cushion defect (7) Ventriculomegaly (5)
Ventricular septal defect (11) Vermian agenesis (2)
Tetralogy of Fallot (2) Duodenal atresia (9)
Double-outlet right ventricle (2) Esophageal atresia (2)
Ebstein anomaly Diaphragmatic hernia
Coarctation of the aorta (3) Omphalocele
Pericardial effusion (2) Hydronephrosis
Pleural effusion (2) Ureteral dilatation
Cystic hygroma (4) Clubfoot
Major anomalies not detected Endocardial cushion defect (4)

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Ventricular septal defect (6)
Coarctation of the aorta (2)
Anomalous pulmonary venous return
Duodenal atresia
Malrotation
Hydronephrosis
Imperforate anus

Note: Data expressed as N (%).

a
In seven pregnancies, the anomaly resolved prior to delivery. Resolved anomalies include ventricular septal defect (3), ventriculomegaly (2), cystic
hygroma, and a pericardial effusion.
b
Both cardiac and noncardiac anomalies were present in seven neonates.

Comment are not generally included in tables of screening test effi-

There were three primary findings from our study of risk
factors identified in second-trimester Down syndrome preg-
nancies. First, from the perspective of population-based
screening for Down syndrome, the sensitivity of second-tri-
mester screening was high—93% among women who received
serum quadruple marker screening and standard sonography.
Second, affected pregnancies were three times more likely to
have multiple risk factors than a single risk factor, 72%
compared with 24%, thus facilitating their detection. Finally,
the majority of Down syndrome pregnancies occurred in
women 35 years and older, and such pregnancies were even
more likely to have additional risk factors identified.
As a component of routine prenatal care, efficacy of Down
syndrome screening is a frequent counseling topic. Second-
trimester quadruple marker screening is generally assumed
to have similar sensitivity to first-trimester screening with
nuchal translucency and serum analytes, of 80%.4 However,
as sonography is recommended at 18 to 22 weeks in all
pregnancies,3 it seems an odd omission that findings from
this sonogram are not considered when evaluating screening
efficacy. Minor ultrasound markers are frequently identified
during standard sonograms, and their detection and man-
agement are addressed in clinical guidelines; however, they
cacy.4 Much of the data regarding the efficacy of second-
trimester sonography for aneuploidy detection are extrapo-
lated from studies of genetic sonograms in pregnancies
identified to be at “high risk.”8,9 Little information is avail-
able describing how standard sonography may improve
aneuploidy detection over serum screening alone. Our data
would suggest that women electing quadruple marker
screening and standard sonography can be informed that
the sensitivity for Down syndrome may be as high as 93%,
perhaps even higher if the patient has an indication for
targeted imaging.
In our series, the sensitivity of standard sonography in
Down syndrome pregnancies—namely, the likelihood that an
affected pregnancy would be identified to have at least one
major anomaly or minor ultrasound marker (or both)—ranged
from just more than 50% in women younger than 35 years at
delivery to more than 75% in older women. Women may find
this information about the utility of sonography helpful. Over-
all, 45% of affected pregnancies had a major structural fetal or
neonatal abnormality identified, when live births and still-
births were considered. Other investigators have reported
similar but varied prevalence, which has ranged from 32 to
64% in population-based series.10–12 The proportion of Down
syndrome pregnancies with major anomalies identified

American Journal of Perinatology

Down Syndrome Risk Factors Hussamy et al.
sonographically in the second trimester is also similar to what
others have reported.5
More than 50% of infants with Down syndrome in our
cohort were born to women 35 years and older. This chal-
lenges common dogma that the majority of Down syndrome
pregnancies occur in younger women simply because more
pregnancies occur in younger women.4 Yet the number of
births to women ages 35 years and older has been steadily
increasing for more than two decades, such that it is 16% in
the United States and 19% across Europe.13–15 Data from the
Centers for Disease Control and Prevention indicate that
women 35 years and older are approximately five times
more likely than women ages 20 to 29 years to have a
pregnancy with fetal Down syndrome, and that women
40 years and older are more than 15 times more likely.16
From a purely mathematical perspective, it is thus not
unexpected that the majority of Down syndrome infants
would be born to women age 35 years and older. The higher
sensitivity of serum aneuploidy screening we observed in
older gravidas is similar to reports by other investiga-
tors.17,18 When taken together with the higher sensitivity
of sonography, 99% of pregnant women 35 years and older
had at least one additional risk factor identified, a sensitivity
that rivals cell-free DNA screening.19
One limitation of our study is that our patient population
may differ from others. The birth prevalence of Down
syndrome that we encountered is higher than the antici-
pated prevalence of 1:800.4 In the EUROCAT network of
population-based registries, the Down syndrome live birth
prevalence is 11.2 per 10,000 or 1:893, but the total pre-
valence—adjusting for pregnancy termination and losses
beyond 20 weeks—is estimated to be 22 per 10,000 or
1:455, comparable to what we identified.14 de Graaf et al
have also estimated what the Down syndrome birth pre-
valence would be in the United States in the absence of
pregnancy termination, yielding projections similar to
what we observed in our population (in which termination
is rarely elected).20 Of women with fetal Down syndrome
who received care at our hospital during the study period,
29% did not elect screening or presented too late in gestation
to receive it, nor did they receive first-trimester screening or
cell-free DNA screening. Kuppermann et al reported that at
least 20% of pregnant women do not elect to receive any
aneuploidy screening, even when financial barriers are
removed.21 We also have an unusually low acceptance rate
for prenatal diagnosis and thus were unable to evaluate how
knowledge of the Down syndrome diagnosis may have
affected pregnancy outcomes such as mode of delivery or
even stillbirth.
An additional limitation is that we assessed only five
categories of minor ultrasound markers as part of standard
sonography. It was not our intent to evaluate the role of the
“genetic” sonogram to further increase or decrease the fetal
aneuploidy risk, as has been well characterized by others.9
Despite this, our results are similar to those of Aagaard-Tillery
et al who used data from the FASTER trial and reported that
genetic sonography improved Down syndrome detection from
81% with quadruple marker screening to 90%.22 Our perspec-
American Journal of Perinatology
tive is that the purpose of population-based aneuploidy
screening is to identify pregnancies at increased risk. We
sought to evaluate the likelihood that affected pregnancies
may come to attention with routine sonographic screening.
While this may underestimate the detection possible with
targeted sonography, it is not currently feasible for all pregnant
women to receive specialized sonography as part of routine
care. Although the choice for aneuploidy screening is diverse
and continues to be an ongoing topic of debate, we can reassure
pregnant women that the sensitivity of routine second trime-
ster screening remains quite high.
Note
This study was presented at the Society for Maternal-Fetal
Medicine 37th Annual Meeting, Las Vegas, NV.
Conflict of Interest
None.
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