Abstract
Purpose
In this study, we aimed to compare the changes in the number, yield, and the percentage of karyotyping indications of the invasive prenatal diagnostic tests between the periods before and after cell-free fetal DNA was introduced to clinical use.
Method
The number of invasive prenatal diagnostic procedures such as amniocentesis and chorionic villus sampling, indication percentages and karyotype results in the periods before (January 1, 2009–December 31, 2010), (n = 1412) and after (January 1, 2016–December 31, 2017), and (n = 593) the introduction of cell-free fetal DNA was retrospectively evaluated.
Results
When compared with the period before cell-free fetal DNA came into clinical use, the number of invasive prenatal diagnostic tests decreased by 58% while their yield was found to have increased (4.4% vs. 10.3%) in the period after cell-free DNA began to be used (p < 0.001). While there was a decrease in the indications due to advanced maternal age, an increase was found in ultrasonography indications for structural anomaly and the risk of a single-gene disorder (p < 0.001). Amniocentesis rate was found to have decreased in invasive prenatal diagnostic procedure types, while an increase was reported in CVS rates (p < 0.001).
Conclusions
Invasive prenatal diagnosis gradually decreases over the years, but the yield of invasive prenatal diagnostic tests increases. In parallel with the rapid development of modern molecular technologies and cheaper and easier access to the tests, we think that the number of invasive prenatal diagnostic tests will experience a more dramatic decrease in the following years.
Keywords: Cell free-fetal DNA, Prenatal invasive test, Aneuploidy, Chromosomal abnormality
Introduction
Invasive prenatal diagnostic procedures, which began to be used in the second half of the twentieth century to detect fetal anomalies, provided the acquisition of fetal cells, enabling us to recognize fetal chromosomal abnormalities [1, 2]. While invasive prenatal diagnostic tests such as amniocentesis (AC) and chorionic villus sampling (CVS) result in very high accuracy in fetal genetic evaluation, they contain risks such as fetal loss, fetal injury, membrane rupture, and maternal infection in different rates for the fetus and the mother [3–6].
Cell-free fetal DNA (cff DNA) has been used in recent years as a high-sensitivity new generation screening test that allows screening of the most common trisomies (21, 18, 13) and aneuploidies related to sex chromosomes through the analysis of cell-free DNA fragments detected in maternal plasma [7, 8]. Cff DNA is considered to be more reliable and accurate than traditional prenatal screening [9]. In a study by Palomaki et al., its sensitivity for trisomy 21, trisomy 18, and trisomy 13 were reported to be 99.1%, 100%, and 91.7%, respectively. The false-positive rates were reported as 0.2%, 0.3%, and 0.9% for trisomy 21, trisomy 18, and trisomy 13, respectively [10]. As a result, international organizations, including the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG), support cff DNA as a routine screening option [11, 12]. Innovations over the years in prenatal screening tests have led to changes in the number and indications of invasive prenatal diagnostic procedures [13, 14]. Especially after the introduction of cff DNA, there has been a decrease in the number of AC and CVS performed for genetic evaluation [15–17].
In our study, we aimed to evaluate and compare the number of invasive prenatal diagnostic tests such as CVS/amniocentesis performed in our reference clinic, the percentage of karyotyping indications, and the rate of cytogenetic abnormality detection per intervention between the periods before cff DNA was introduced to clinical use (2009–2010) and after its introduction (2016–2017).
Methods
In the current study, the number, indication percentages, and karyotype results of invasive prenatal diagnostic tests such as AC and CVS conducted in the Department of Obstetrics and Gynecology, School of Medicine, Ege University, in the periods before and after the introduction of cff DNA into clinical use were retrospectively evaluated. The period between January 1, 2009, and December 31, 2010, was selected as the pre-cff DNA period (n = 1412), and the period between January 1, 2016, and December 31, 2017, was selected as the period after the introduction of cff DNA (n = 593). Since cff DNA was offered for clinical use in 2011, the years 2009–2010 were selected for the pre-cell-free period. The dates 2016–2017 were selected for the post-cell-free period because the cff DNA test has been accessible in another hospital in our region since 2016 as part of medical indication, totally covered by the social security institution, and without any additional payment by the patient. The local ethics and research committee approval was obtained for the study (registration number: 20-1.1 T/30).
In our study, invasive prenatal diagnostic tests performed before and after cff DNA came into clinical use were analyzed and compared in terms of the following characteristics. The indication of the invasive prenatal diagnostic test was evaluated and compared in terms of whether the karyotype result was normal, the type of chromosomal abnormality if a chromosomal abnormality was detected, and the number of invasive prenatal diagnostic tests required to detect a chromosomal abnormality.
Indications for the invasive prenatal diagnostic procedure are classified as advanced maternal age (AMA); first or second-trimester-positive screening test; detection of soft marker or structural anomaly on ultrasonography; parents carrying single-gene disorders such as thalassemia, spinal muscular atrophy (SMA), and cystic fibrosis; maternal anxiety; parent carrying balanced translocation; and a history of baby with trisomy.
The cases with indications for cff DNA were grouped as advanced maternal age, a positive first or second-trimester screening test, single soft marker on ultrasonography, maternal anxiety, and a history of baby with trisomy, while suspected single-gene disorder, structural anomalies on ultrasonography, suspected fetal infection, presence of balanced translocation in parents, and multiple pregnancies were not considered as indications for cff DNA.
In the ultrasonographic examination, increased nuchal translucency, absence of nasal bone, echogenic intestine, pyelectasis, short long bones (humerus, femur), echogenic intracardiac focus, and choroid plexus cysts were evaluated as soft markers.
Statistical analysis
Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL, USA) version 20.0. Student’s t test was used to evaluate differences between groups. Results are presented as the mean ± standard error of the mean. All categorical variables were calculated using the chi-square test. p < 0.05 was considered as statistically significant.
Results
While an invasive prenatal diagnostic test was performed on 1412 patients in the pre-cff DNA period, 593 patients underwent an invasive prenatal diagnostic test in the period following the introduction of cff DNA. The main demographic characteristics of the patients are demonstrated in Table 1. There was nearly a 58% decrease in invasive prenatal diagnostic tests. Mean maternal age in the periods before and after cff DNA came into use was found to be 33.02 ± 5.94 and 32.6 ± 6.2, respectively, and there was no significant statistical difference between the groups in terms of maternal age (p; 0.313). The comparative numbers and indication percentages of invasive prenatal diagnostic tests performed in both periods are shown in Table 2.
Table 1.
Demographic characteristics of the patients
| Before cff DNA (n = 1412) | After cff DNA (n = 593) | p value | |
|---|---|---|---|
| Age (y) | 33.02 ± 5.94 | 32.6 ± 6.2 | 0.313 |
| Week of invasive prenatal diagnosis | 17.74 ± 2.68 | 16.14 ± 5.27 | < 0.001 |
| Gravidity (n) | 2.33 ± 1.31 | 2.32 ± 1.08 | 0.887 |
| Abortion (n) | 0.55 ± 0.93 | 0.39 ± 0.70 | < 0.001 |
y, years, n, number, cff DNA, cell-free fetal DNA
Data are expressed as mean ± standard error of the mean
All italic p values are expressed as significant
Table 2.
The comparative numbers and indication percentages of invasive prenatal diagnostic tests performed before and after cff DNA
| Indications | Before cff DNA (n; %) | After cff DNA (n; %) | p value | ||
|---|---|---|---|---|---|
| Candidate for cff DNA | |||||
| AMA | 491 | 34.77% | 124 | 20.91% | < 0.001 |
| First/second trimester screening test positivity | 591 | 41.85% | 249 | 41.98% | 0.956 |
| Soft marker in ultrasonography | 64 | 4.53% | 35 | 5.90% | 0.196 |
| Maternal anxiety | 14 | 0.99% | 1 | 0.16% | 0.051 |
| History of baby with trisomy | 18 | 1.27% | 7 | 1.18% | 0.86 |
| Total number of candidate for cff DNA | 1178 | 83.4% | 416 | 70.1% | < 0.001 |
| Non-candidate for cff DNA | |||||
| Single gene disorders (SMA, Cystic fibrosis, Thalassemia) | 132 | 9.34% | 93 | 15.68% | < 0.001 |
| Ultrasound abnormality | 60 | 4.24% | 66 | 11.12% | < 0.001 |
| Infection | 8 | 0.56% | 4 | 0.67% | 0.775 |
| Parental balanced translocation carrier | 5 | 0.35% | 5 | 0.84% | 0.156 |
| Multiple pregnancy | 29 | 2.05% | 9 | 1.51% | 0.422 |
| Total number of noncandidate for cff DNA | 234 | 16.6% | 177 | 29.9% | < 0.001 |
| Total | 1412 | 100% | 593 | 100% | |
AMA, advanced maternal age, cff DNA, cell-free fetal DNA
All italic p values are expressed as significant
When patients who are not candidate for cff DNA (single-gene disorders, balanced translocation carriers, multiple pregnancies, a structural anomaly in ultrasonography) in either period are excluded, the number of invasive prenatal diagnostic tests performed during the periods before and after cff DNA is 1178 and 416, respectively. 16.57% of invasive prenatal diagnostic tests in the pre-cff DNA period and 29.84% of those in the post-cff DNA period consisted of patients who could not be candidates for cff DNA, which was a statistically significant increase (p < 0.001). When the indications of the invasive prenatal diagnostic test were evaluated, the most common indications were found to be cases with positive first and second-trimester screening tests and cases with AMA, respectively, in both groups.
An evaluation of both periods revealed a statistically significant decrease in invasive prenatal diagnosis tests performed due to AMA (34% vs. 21%; p < 0.001). The rate of invasive prenatal diagnostic tests performed due to positive first and second-trimester screening test results was similar in both periods and there was no statistically significant difference (p; 0.956). In cases such as single soft marker detection in ultrasonography, history of a baby with trisomy, and maternal anxiety, there was no statistically significant difference between the two periods. The rate of invasive prenatal diagnostic tests performed due to structural anomaly in ultrasonography (4.2% vs. 11.1% p < 0.001) and risk of single-gene disorders (9.3% vs. 15.6% p < 0.001) showed a statistically significant increase in the post-cff DNA period when compared with the pre-cff DNA period. There was no significant difference between two periods in the rates of invasive prenatal diagnostic tests performed due to balanced translocation in one of the parents and suspicion of fetal infection.
Of the 1412 invasive prenatal diagnostic tests performed in the pre-cff DNA period, 4.4% (n = 62) of the cases had cytogenetic abnormalities. In the post-cff DNA period, 593 invasive prenatal diagnostic tests were carried out, and cytogenetic abnormalities were detected in 10.3% (n = 61) of them. Considering the detection rates in both periods, a statistically significant difference was found (p < 0.001). There was no significant change in the rate of cytogenetic anomaly types (sex chromosomes, major trisomies, and other trisomies, triploidy, balanced and unbalanced translocations) between both periods. Cytogenetic findings for both periods are shown in Table 3. The number of invasive prenatal diagnostic tests performed to detect 1 cytogenetic anomaly or 1 major trisomy (13, 18, 21) case showed a significant decrease in the period following the introduction of cff DNA. The comparison of the two periods is presented in Tables 4 and 5.
Table 3.
Cytogenetic findings before and after cff DNA
| Variables | Before cff DNA | After cff DNA | p value | ||
|---|---|---|---|---|---|
| (n = 1412) | (n = 593) | ||||
| No cytogenetic abnormality | 1350 | 95.6% | 532 | 89.7% | < 0.001 |
| Cytogenetic abnormality | 62 | 4.4% | 61 | 10.3% | < 0.001 |
| Cytogenetic abnormality | (n = 62) | (n = 61) | |||
| Trisomy 21, 18, 13 | 37 | 59.6% | 36 | 59% | 0.941 |
| Sex chromosome | 5 | 8% | 6 | 9.8% | 0.731 |
| Other trisomy, triploidy, balanced and unbalanced translocations | 20 | 32.2% | 19 | 31.1% | 0.895 |
Cff, cell-free fetal DNA
All italic p values are expressed as significant
Table 4.
Number of invasive prenatal diagnostic tests to detect one cytogenetic abnormality
| Period | Invasive test (n) | Chromosomal abnormality (n) | Number of invasive test to detect one-cytogenetic abnormality |
|---|---|---|---|
| Before cff DNA | 1412 | 62 | 22.8 |
| After cff DNA | 593 | 61 | 9.7 |
Cff DNA, cell-free fetal DNA
Table 5.
Number of invasive prenatal diagnostic tests to detect one major trisomy
| Period | Invasive test (n) | Trisomy 21, 18, 13 (n) | Number of invasive test to detect one major trisomy |
|---|---|---|---|
| Before cff DNA | 1412 | 37 | 38.1 |
| After cff DNA | 593 | 36 | 16.4 |
While AC was performed in 1309 cases and CVS was performed in 103 cases as an invasive prenatal diagnostic test in the pre-cff DNA period, 520 cases underwent AC, and 73 cases underwent CVS in the post-cff DNA period, which shows a decrease in the rate of AC and an increase in CVS rate. These differences were statistically significant in both AC and CVS rates (p < 0.001). The period comparison of invasive prenatal diagnostic tests is demonstrated in Table 6.
Table 6.
Comparison of the number of prenatal invasive tests before and after cff DNA
| Type of prenatal invasive test | Before cff DNA (n; %) | After cff DNA (n; %) | p value |
|---|---|---|---|
| AC | 1309; 92.7% | 520; 87.7% | < 0.001 |
| CVS | 103; 7.3% | 73; 12.3% | |
| Total | 1412 | 593 |
AC, amniocentesis; CVS, chorion villus sampling; Cff DNA, cell-free fetal DNA
Discussion
In the present study, we found statistically significant decrease in invasive prenatal diagnostic tests upon a comparison of the periods before and after cff DNA came into clinical use. Our findings are compatible with other studies in the literature [18–20]. When the indications for invasive prenatal diagnostic tests were compared, the most obvious difference was found to be the decrease in prenatal diagnostic tests performed due to AMA in the post-cff DNA period. As far as we know, one of the reasons for this is that the cff DNA test upon the indication of AMA is performed in another hospital in our region, totally covered by the social security institution, without any additional payment by the patient [21].
When both periods were compared, a significant difference was found in the number of abortion and in the week of gestation in which the invasive prenatal diagnostic test was applied. The reason for the decrease in the post-cff DNA period during the week of gestation in which the invasive prenatal diagnostic test was applied might be that the CVS procedure was performed at a higher rate than the post-cff DNA period. The fact that the number of abortion was lower in the post-cff DNA period might be due to the fact that the cases with high abortion number preferred cff DNA.
Positive first or second trimester screening result was the most common invasive prenatal diagnostic test indication in both periods, and no significant difference was observed between the study periods. The analysis of the changes in the number of prenatal diagnostic tests performed due to positive first or second-trimester screening indications in the literature showed that some studies did not find a significant difference [16], while some others identified a decrease in the post-cff DNA period [18]. While 83% of the cases in the pre-cff DNA period indicated for cff DNA, this rate was found to be significantly low at 70% in the post-cff DNA period. Whereas there was a significant difference in AMA as an indication for cff DNA, no significant difference was observed in terms of indications, such as positive screening test result, soft marker in ultrasonography, maternal anxiety, and chromosomal trisomy.
A significant increase was found in the percentage of cases with the single-gene disorder and structural anomaly in ultrasonography in the post-cff DNA period in the group, which had no indications for cff DNA. We believe that the increase in the number of prenatal tests performed due to structural anomaly in ultrasonography is considered due to the fact that pregnant women can easily access ultrasonography. In invasive prenatal diagnostic tests performed due to the suspicion of fetal infection and parents who are carriers of balanced translocation, no significant difference was detected between the two periods. Likewise, there was no significant difference between the periods in invasive prenatal diagnostic tests performed due to a history of baby with trisomy. Although there was a decrease in invasive prenatal diagnostic tests performed specifically due to maternal anxiety, no statistical significance was found (0.99% vs. 0.16% p; 0.051). While cytogenetic anomaly was detected in 4.4% of invasive prenatal diagnostic tests performed in the pre-cff DNA period, this rate increased to 10.3% in the post-cff DNA period. As invasive prenatal diagnostic tests have fetal and maternal risks, we believe that this increase in improvement may, to some extent, be attributed to the fact that some cases for whom invasive prenatal diagnostic tests were recommended opted for cff DNA and refused further evaluation due to a negative test result. Another factor that improves the yield of invasive prenatal diagnostic tests is the increased rate of detection of structural abnormalities via ultrasonography. Our findings are compatible with recent studies in the literature [22, 23]. We found that approximately 31% of the cytogenetic anomalies detected during the study period consisted of triploids, other trisomies (except 13, 18, 21), and balanced and unbalanced translocations. As a result, we found that 31% of cytogenetic abnormalities detected during the study periods would have gone undetected if only cff DNA was used for diagnostic testing. Currently, none of the professional guidelines recommend routine screening for any of these genetic disorders [11]. These findings are compatible with previous studies [16, 24].
In the post-cff DNA period, the number of invasive prenatal tests required to detect a major trisomy (21, 18, 13) showed a notable decrease compared with the pre-cff DNA period (pre-cff DNA: 1/38 vs. post-cff DNA: 1/16). Li et al. stated in their study that the number of invasive prenatal tests required to detect a major trisomy showed a significant decrease in the post-cff DNA period and after the reduction of its price [25]. We reckon that these rates will be further reduced with an increase in accessibility as a result of the further decrease in its price. While AC was the main invasive prenatal test procedure applied in both periods, there was a significant decrease in the number of AC and a significant increase in the rate of CVS in the post-cff DNA period. Similarly, the study by Stevens et al. showed that in the post-cff DNA period, the number of amniocenteses decreased while the number of CVS increased [26]. This increase probably resulted from the implementation of early screening methodologies, increased awareness for single-gene disorders, and the clinical use of cff DNA. The gradual decrease in the number of invasive prenatal diagnoses may lead to a shortage of experienced physicians to perform such procedures in the future. The Royal College of Obstetricians and Gynecologists (RCOG) recommends at least 30 ultrasound-guided invasive procedures per year to maintain competence in clinicians [27]. Given the severe decline in invasive prenatal diagnostic procedures, practitioners in prenatal diagnosis should address the challenges of adequate training and skill maintenance by developing new solutions such as simulation training [22].
The main strengths of our study are that the cff DNA test upon indication is free and accessible in another hospital in our region since the social security institution compensates all costs without requesting any additional payment from the patient [21]. Thus, our data became more homogeneous due to the accessibility of the cff DNA test to a group of patients who would not be able to afford it otherwise. The limitations of our study include the assumption that all the changes in the rate and indications of invasive prenatal diagnostic tests in both periods are the result of the use of cff DNA test, and the lack of precise information on how many cases took the cff DNA test after being recommended in the post-cff DNA period during the counseling. The growth and development of the fetus in the maternal abdomen prevent the fetus from being accessible and thus increases the chance of survival for the single fetus. All kinds of fetoplacental interventions even if it is minimally, particularly invasive prenatal diagnostic procedures, reduce this chance. Therefore, it will not be difficult to predict that cff DNA, with its high sensitivity and specificity, will become the basic test in prenatal screening when it is more affordable, reducing the number of unnecessary invasive prenatal diagnostic tests.
In summary, the number of expectant mothers who undergo invasive prenatal diagnostic tests decreases over the years, but the efficiency of invasive prenatal diagnostic tests increases. We think that the introduction of cff DNA into clinical use is the main factor in this situation. In parallel with the rapid development of modern molecular technologies and cheaper and easier access to the tests, we reckon that the number of invasive prenatal diagnostic tests will decrease much more dramatically in the following years. We anticipate that the current cff DNA test will become more widespread if the limitations are overcome, and the test reaches diagnostic test criteria through technical corrections. However, even if the cff DNA test becomes the primary diagnostic tool through all the corrections, there might still be indications that require confirmation with invasive tests, albeit few.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Footnotes
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