Keywords
abortion - amniocentesis - chorionic villi sampling - chromosomal microarray - prenatal
genetic screening - single gene disorders
About 1 in every 150 live births has a chromosomal abnormality that causes an abnormal
phenotype in the fetus or neonate.[1] Prenatal genetic screening and diagnostic testing provide pregnant women with information
that could lead some to consider terminating the pregnancy. Advances in prenatal genetic
screening have enabled common chromosomal abnormalities to be suspected in the first
trimester, with diagnosis achievable at <14 weeks' gestation in most cases.
Both the American College of Obstetricians and Gynecologists (ACOG) and the Society
of Maternal-Fetal Medicine (SMFM) have stated that prenatal genetic screening and
invasive testing by chorionic villi sampling (CVS) or amniocentesis should be offered
to any pregnant woman, regardless of age and risk factors.[2]
[3]
[4] ACOG and SMFM have also recommended that with appropriate genetic counseling, chromosomal
microarray (CMA) testing can be offered to all women undergoing diagnostic testing,
especially in cases in which a fetal structural abnormality is detected.[5]
[6] Another recent change in practice is the availability of expanded carrier screening
for both parents, beyond screening for cystic fibrosis, spinal muscular atrophy, fragile
X permutation, and conditions related to ethnicity when appropriate.[7]
[8] When parents are found to be carriers of certain single-gene disorders, advances
in sequencing techniques have made it possible to achieve early prenatal diagnosis
through invasive testing.[9]
These advances have enabled patients to not only have earlier genetic diagnosis but
also earlier abortion when desired. A 2017 series conducted from 2004 to 2014 found
that for women undergoing abortion for fetal aneuploidy, median gestational age (GA)
at the time of abortion decreased from 19 to 14 weeks, but women who underwent abortion
for fetal structural abnormalities did not have a decrease in GA at the time of abortion.[10] A study performed at our institution looking at timing of prenatal diagnosis and
abortion over a 10-year period found that, with the increasing use of cell-free DNA
(cfDNA) testing, the GA at prenatal diagnosis and abortion for Turner's syndrome (TS)
21 declined significantly, with most cases diagnosed in the first trimester in the
most recent study interval.[11] Abortions performed in the first trimester or early second trimester are technically
easier to perform, are less time consuming, and carry less risk for the patient.[12]
Although advances in screening have led to earlier diagnosis and abortion, we cannot
screen for all genetic conditions associated with abnormal development. In some cases,
prenatal diagnosis occurs only after a structural abnormality is detected on ultrasound,
often not until the second trimester. Other abnormalities, including copy number variants,
may not be associated with any ultrasound findings, and may only be detected in “low-risk”
patients who elect to undergo amniocentesis or CVS to have access to the best information.
In this study, our objective was to compare the GA at diagnosis and abortion for genetic
abnormalities amenable to routine prenatal screening versus genetic abnormalities
that cannot be suspected based on available screening tests. Our hypothesis was that
the GAs at prenatal diagnosis and abortion are greater for uncommon genetic abnormalities
not likely to be picked up by prenatal genetic screening.
Methods
This was a retrospective database review of all prenatal diagnostic procedures performed
in our ultrasound unit from 2012 to 2017. This study was approved by our institution's
Institutional Review Board. Patients who underwent abortion after diagnosis of a genetic
abnormality were included. We compared cases of abortion with a diagnosis of a condition
screened for during pregnancy with the remaining cases. Our primary outcome was GA
at abortion. We only included patients who chose to terminate their pregnancy as timing
of prenatal diagnosis is most relevant in these patients.
Cases included in the “screened” group included those with prenatal diagnoses of common
chromosomal abnormalities (trisomies 21, 18, and 13, triploidy, and sex chromosome
abnormalities including 45X, 47XXY, 47XXX, and 47XYY), conditions identified through
parental carrier screening, and cases in which prenatal testing was done due to a
known family history. Screening tests included nuchal translucency (NT), first- and
second-trimester serum screening tests, and cfDNA testing. As NT is used as a nonspecific
genetic screening tool, any chromosomal abnormality, CMA abnormality, or mutation
associated with Noonan's syndrome diagnosed after abnormal NT was categorized with
the “screened” group. All other cases which involved genetic conditions that could
not have been suspected based on aneuploidy screening, carrier testing, or family
history were categorized as “unscreened.” CMA abnormalities were included only when
they were considered pathogenic, not if they were considered variants of unknown significance.
When invasive testing was performed without a positive screening test (most commonly
in women age ≥35 years), cases with a diagnosis of common chromosomal abnormalities
were assigned to the “screened” group,, as screening tests with high sensitivity are
available for these conditions. Group assignment was made based on the genetic diagnosis,
and not based on the specific screening tests performed on individual patients. For
example, patients who were screened with NT and cfDNA that was normal but had a diagnosis
of a CMA abnormality when amniocentesis was performed following an abnormal ultrasound
finding were assigned to the “unscreened” group. Patients who underwent CVS without
prior screening and had a common autosomal trisomy diagnosed were assigned to the
“screened” group. All patients with abnormal genetic results were counseled by genetic
counselors, with the option of referral to pediatric geneticists if requested.
Fisher's exact test and Mann–Whitney U test were used for statistical comparison. A p-value of <0.05 was considered statistically significant. Continuous data are expressed
as median (interquartile range).
Results
There were 268 cases of abortion included in the study, and all patients underwent
diagnostic testing via CVS or amniocentesis. A total of 227 (85%) were performed for
genetic disorders considered to be “screened.” Most abortions for “screened” conditions
were performed due to karyotype abnormalities (93%). The remainder was performed for
single-gene disorders (5%) and CMA abnormalities (2%). The most common karyotype abnormality
was TS 21 (46%) followed by TS 18 (16%), TS 13 (10%), and TS (4%).
The remaining 41 cases (15%) were abortions performed for genetic disorders that were
not detected as a result of any screening process. The most common type of genetic
finding in this group was CMA abnormalities (61%), followed by uncommon karyotype
abnormalities (19%) and single-gene disorders (19%) ([Fig. 1]). Abnormal sonographic findings were found in 19 (46%) of these cases overall, and
were significantly more common in cases with single-gene disorders (100%) compared
with CMA abnormalities (40%) or chromosomal abnormalities (11%) (p < 0.001) ([Table 1]).
Table 1
Genetic abnormalities of abortions performed for disorders that were not screened
for
|
Unscreened genetic abnormalities
|
|
Ultrasound findings
|
GA abortion (wk)
|
|
Karyotype abnormality (N = 8)
|
|
Mosaic TS 8
|
None
|
196/7
|
|
Mosaic TS 8
|
None
|
192/7
|
|
Mosaic TS 9
|
None
|
174/7
|
|
Mosaic TS 9
|
None
|
172/7
|
|
Mosaic TS 16
|
None
|
200/7
|
|
Mosaic TS
|
None
|
140/7
|
|
Mosaic tetraploid/diploid
|
Micrognathia, bilateral clubfoot, echogenic kidneys
|
145/7
|
|
Mosaic tetraploidy
|
None
|
180/7
|
|
CMA finding (N = 25)
|
|
Terminal mosaic deletion of 4p and terminal mosaic duplication of 10q
|
None
|
132/7
|
|
Isodicentric chromosome 14
|
None
|
162/7
|
|
Ring chromosome 18
|
None
|
132/7
|
|
Pericentric inversion of Y
|
None
|
110/7
|
|
Balanced transl 2 and 10
|
None
|
174/7
|
|
Duplication chromo 10
|
None
|
140/7
|
|
Unbalanced transl 8 and 21
|
None
|
132/7
|
|
Del 9q34.3 (Kleefstra's syndrome)
|
Choroid plexus cysts, echogenic bowel, bilateral renal pyelectasis, absent nasal bone
|
223/7
|
|
Unbalanced transl 21q and 10q
|
Agenesis of corpus callosum, bilateral cleft lip
|
230/7
|
|
5p duplication
|
Bilateral clubfoot
|
230/7
|
|
Duplication of chromosome 3, UPD chromosome 12
|
Lagging growth, inferior cerebellar vermian agenesis
|
225/7
|
|
11p deletion (WAGR syndrome)
|
Ambiguous genitalia
|
222/7
|
|
Unbalanced recombinant chromosome 16
|
Bilateral clubfoot, cardiac abnormality, lagging growth
|
254/7
|
|
22q11 deletion
|
Cardiac abnormality (truncus arteriosus)
|
210/7
|
|
Chromosome 15 duplication
|
Unilateral preaxial polydactyly
|
230/7
|
|
UPD chromosome 4
|
Ventriculomegaly, lagging growth (MRI: intracranial hemorrhage)
|
222/7
|
|
16p11 duplication
|
None
|
192/7
|
|
Chromosome 7 deletion
|
None
|
220/7
|
|
22q duplication
|
None
|
133/7
|
|
17q12 duplication
|
None
|
225/7
|
|
Mosaic interstitial deletion of 11Q12
|
None
|
185/7
|
|
Interstitial deletion of homolog of chromosome 1
|
None
|
234/7
|
|
Mosaic duplication chromosome 11
|
None
|
132/7
|
|
Single-gene disorder (N = 8)
|
|
FGR2 mutation (Apert's syndrome)
|
Syndactyly, brain abnormalities
|
224/7
|
|
FOXC2 mutation
|
Pedal edema
|
210/7
|
|
TD1 mutation (skeletal dysplasia)
|
Severe micromelia, bowing
|
175/7
|
|
TSC1 mutation (tuberous sclerosis)
|
Cardiac rhabdomyomas
|
234/7
|
|
FGR mutation (skeletal dysplasia)
|
Short long bones, lagging growth
|
300/7, a
|
|
TSC1 mutation (tuberous sclerosis)
|
Cardiac rhabdomyomas
|
325/7, a
|
|
TD2 mutation (thanatophoric dysplasia)
|
Micromelia, bilateral clubfoot
|
200/7
|
|
FGR3 mutation (thanatophoric dysplasia)
|
Short long bones, bowing, bell-shaped chest
|
162/7
|
Abbreviations: CMA, chromosomal microarray; GA, gestational age; MRI, magnetic resonance
imaging; TS, Turner's syndrome.
a In these cases, abortion was delayed due to twin pregnancy.
Fig. 1 Types of genetic disorders in the two study groups: abortions performed for “screened
for” conditions and abortions performed for not “screened for” conditions.
There were 31 women (12%) who either had negative screening or had no screening for
chromosomal abnormalities, with the listed indication for invasive testing as “advanced
maternal age” for 25 (80.6%) of them. The median age in this group was 37 years. CVS
was performed in 18 of these cases (58%) and amniocentesis in 13 (42%). Common chromosomal
abnormalities were identified in nine cases, and assigned to the “screened” group.
Of these 31 women, 22 (71%) were in the unscreened group, and copy number variants
were detected in most of these cases (82%).
Invasive testing by CVS or amniocentesis and abortion occurred at earlier median GA
for those with conditions that were screened for: 122/7 versus 155/7 weeks (p ≤0.001) and 135/7 versus 200/7 weeks (p ≤0.001). The median procedure-to-abortion interval was significantly longer in the
cases of abortions performed for conditions in the “unscreened” group compared with
the screened group (12/7 vs. 30/7 weeks, p < 0.001) ([Table 2]).
Table 2
GA at the time of invasive procedure and abortion
|
Abortions performed for abnormalities that were screened for
|
Abortions performed for abnormalities that were not screened for
|
p-Value
|
|
Maternal age (y, IQR)
|
37 (34–40)
|
35 (33–39)
|
0.225
|
|
GA at invasive procedure (wk)
|
122/7 (115/7–126/7)
|
155/7 (121/7–191/7)
|
<0.001
|
|
GA at abortion (wk)
|
135/7 (130/7–151/7)
|
200/7 (150/7–225/7)
|
<0.001
|
|
Procedure-to-abortion interval (wk)
|
12/7 (06/7–20/7)
|
30/7 (14/7–54/7)
|
<0.001
|
Abbreviations: GA, gestational age; IQR, interquartile range.
Note: Data represented as median (interquartile range).
There were 27 abortions performed at ≥20 weeks' gestation, representing 10% of women
terminating pregnancies due to genetic abnormalities. Of these, 19 (70%) were in the
“unscreened” group, representing nearly half of the cohort that were not screened
for the genetic abnormality detected. These included 12 (63%) CMA abnormalities, 6
(32%) single-gene disorders, and 1 (5%) karyotype abnormality. In the eight cases
of abortion performed ≥20 weeks' gestation in the “screened” group, three (38%) were
performed for TS 21, two (25%) for Noonan's syndrome, two (25%) for TS 18, and one
(12%) for TS 13. Of the five chromosomal abnormalities in the “screened” group, four
were for autosomal trisomy with false-negative screening, and one entered prenatal
care at 17 weeks and therefore did not have first-trimester screening.
Discussion
In our population, prenatal diagnosis and abortion for genetic conditions amenable
to screening occurred primarily in the first and early second trimesters. In contrast,
prenatal diagnosis and abortions performed for abnormalities that were not screened
for occurred at significantly later GAs, with abortion occurring at a median GA of
20 weeks. The interval between diagnostic procedure and abortion was also significantly
longer for unscreened conditions, which is likely to reflect the increased time for
laboratories to complete CMA and mutation testing. It is also likely that the lack
of a clear phenotype associated with many CMA findings contributed to this longer
interval, as patients may have sought genetic counseling and taken longer to reach
a decision to terminate the pregnancy.
Our results are consistent with other studies that have demonstrated that as our ability
to screen for the most common genetic abnormalities advances, the GA at the time of
abortion has significantly declined. In those with conditions not detected by screening,
ultrasound played an important role. Nearly half of the genetic conditions diagnosed
in the “unscreened” cohort, including all with single-gene disorders, had structural
abnormalities identified by ultrasound. In patients who would consider terminating
a pregnancy for structural or genetic abnormalities, ultrasound earlier in the second
trimester could lead to earlier prenatal diagnosis and abortion. This is especially
important when there are strict GA limits on abortion, as CMA or single-gene disorder
testing can take weeks to complete. Our results also suggest that a more detailed
first-trimester ultrasound, which is more frequently performed in countries outside
of the United States, may be able to diagnose major anomalies even earlier in gestation.
A systematic review and meta-analysis recently found that up to 60% of fetal anomalies
can be detected in the first trimester, which suggests that the development of international
protocols with standard anatomic views can be undertaken to optimize first-trimester
anomaly detection.[13] The detection of first-trimester fetal anomalies would likely result in earlier
invasive testing and, subsequently, abortion at an earlier GA.
Some patients may consider invasive testing with normal screening results or without
any screening. In our patients, 12% of abortions for fetal genetic conditions were
in women without abnormal screening, and CMA abnormality was the most common type
of abnormality. Most of these cases did not have ultrasound abnormalities. We practice
in the northeast part of the country, where the rate of abortion is one of the highest
in the country.[14] This may explain why many of the patients in our population seek invasive testing,
often with the intent to terminate a genetically abnormal pregnancy. This may help
explain why there were a significant amount of patients in our study who underwent
invasive testing with no risk factors for having a genetically abnormal fetus. It
is important to counsel patients about the limitations of genetic screening, and the
fact that many conditions will not have sonographic findings but may still be associated
with an abnormal phenotype. A large multicenter study identified a 1.3% rate of pathogenic
or potentially pathogenic copy number variant in women undergoing invasive testing
for “advanced maternal age.” As CMA abnormalities are not known to be age related,
this may reflect the risk in a general population.[15] Patients who may be considered “low risk” for a genetic abnormality should not be
discouraged from undergoing invasive testing in pursuit of more information. If a
patient who would consider abortion is intent on undergoing invasive testing, CVS
should be recommended to achieve the earliest possible diagnosis, as diagnosing and
evaluating copy number variants are a longer process compared with common chromosomal
abnormalities.
One of the strengths of this study was that it only included patients with a prenatal
genetic diagnosis who chose to terminate the pregnancy. Thus, we did not need to speculate
about the clinical impact of prenatal diagnosis in individual patients. The fact that
patients in this study had their prenatal screening for chromosomal abnormalities,
prenatal care, and pregnancy terminations at our institution enabled us to obtain
precise information about the timing of prenatal diagnosis and abortion. These are
clinically relevant outcomes, due to clear advantages in safety and availability of
earlier abortion.
A limitation of this study is its retrospective design, which limited our ability
to evaluate reasons for variation in decisions regarding timing of diagnosis and abortion
between individuals. It is possible that a patient and/or physician's personal beliefs
may have contributed to the delay between genetic diagnosis and abortion, and this
information may not be reflected in the medical record. The study design is also a
potential source of selection bias. Women who did not undergo a termination of pregnancy
following the diagnosis of a genetic abnormality were not included, and these cases
are not necessarily representative of all prenatally detected fetal genetic abnormalities.
Another limitation is that our study does not include patients in whom genetic conditions
were not identified, and we thus cannot determine the efficacy of prenatal screening
and diagnosis in identifying all clinically significant genetic conditions. As most
abnormalities in women without an abnormal screening test were in the “unscreened”
group, it is likely that we are underestimating the true genetic disease burden attributable
to uncommon conditions. Higher rates of “elective” CVS or amniocentesis in low-risk
women are more likely to detect “unscreened” conditions such as CMA abnormalities.
In summary, our study highlights the achievements of prenatal screening for common
chromosomal abnormalities as well as conditions identified by carrier testing, while
also illustrating fact that a significant proportion of conditions not amenable to
screening are unlikely to be diagnosed early in pregnancy. As some pathogenic conditions
may not be suspected based on screening or ultrasound, any woman who might consider
abortion for a genetic condition should consider invasive testing.
