Introduction :
Prenatal diagnosis of chromosomal anomalies includes a variety of techniques either as a screening procedure for relatively prevalent disorders or as a diagnostic procedure for known familial conditions. Approximately 3 percent of live births are affected by a major structural malformation.These defects can be caused by genetic abnormalities and/or environmental exposures. Currently available prenatal non-invasive screening tests are ultrasonography and various biochemical tests, while CVS, amniocentesis, and fetal blood sampling are invasive diagnostic procedures.
High-risk pregnancies :
1. Advanced maternal age (age 35 years or more at estimated date of delivery). Some authors also consider paternal age of approximately 50 years or older.
2. Family history of previous birth of a child with chromosome abnormality / multiple structural defects / ONTDs, or metabolic disorder.
3. Suspicious biochemical results.
4. Abnormal morphological scan.
5. Parent with a chromosome disorder.
6. Parent who are carriers of specific genetic defects such as cystic fibrosis, Tay-Sach dystrophy, sickle cell anemia and thalassaemia.
Types of chromosomal abnormalities:
Chromosomal abnormalities may be numerical or structural.
Numerical chromosomal anomalies are divided into:
1- polyploidy as
triploidy ( a fetus with 69 chromosomes) and
tetraploidy where the fetus has 92
chromosomes. Polyploidy leads to severe congenital anomalies and early abortion.
2- Aneuploidy (one
or more chromosomes is added or missed) as in:
Down syndrome (trisomy 21),
Structural
chromosomal anomalies
include chromosomal deletion, duplication, translocation, inversion, and ring
and iso chromosomes. It may also lead to severe congenital anomalies or fetal death.
The most common reason for prenatal diagnosis of chromosome abnormalities is to look for evidence of trisomies, Turner syndrome and triploidy. Trisomy 13, 18, and 21 are the most common, with trisomy 21 comprising about half of all the trisomies identified.
Screening procedures :
Non invasive diagnostic procedures :
1.Ultrasonography
It is non-invasive and has no inherent procedure related loss. First-trimester sonography is offered mainly to confirm the gestational age, to identify singleton or multiple pregnancy and to measure nuchal thickness (NT). Second-trimester ultrasound is generally recommended at 19 to 21 weeks to detect fetal structural defects. Nuchal translucency (NT) : NT refers to the subcutaneous space between the skin and the cervical spine in the fetus. The ultrasonographic findings of NT in the first-trimester of the pregnancy reportedly has been associated with fetal chromosome abnormalities including trisomies 21,18,13 and triploidy and Turner syndrome (45XO). Among karyotypically normal fetuses increased NT may be related to certain birth defects including cardiac septal defects, diaphragmatic hernia, renal defects, omphalocele, body-stalk anomaly, fetal akinesia syndrome, and certain skeletal dysplasias. Certain genetic defects and infections may also lead to increased NT. Various genetic defects associated with increased NT are Arthrogryposis, Noonan's syndrome, Smith-Lemli-Opitz syndrome, Stickler syndrome, Jarco-Levine syndrome, Miller-Dieker syndrome. Increased NT may be found in a normal fetus. Therefore, increased NT does not mean that the fetus is chromosomally abnormal but it does mean an increased risk for some disorders and birth defects. NT measurements can be taken from the sagittal section of the fetus usually used to obtain the crown-rump length, or from a transverse suboccipitobregmatic view of the fetal head. NT values are crown-rump-length-dependent. Measurements equal to or more than 3mm in the first-trimester and more than 6mm in the second-trimester are considered as abnormal. NT is apparently a powerful tool for the detection of aneupolidy, particularly Down's syndrome. For isolated nuchal edema, the risk for trisomy 21 may be 15 times the background. The estimated detection rate for Down's syndrome using NT at 10 to 14 weeks of gestation combined with maternal age is about 80% at a cut off risk of 1 in 300 or higher. However, there is considerable disagreement in the literature as to the precise Down's syndrome detection rate that can be expected with this form of sonography. Cystic hygroma is caused by the malformation of the fetal lymphatic system and is found commonly in fetuses with Monosomy X (Turner syndrome), and other chromosomal anomalies. An important part of evaluation of nuchal membrane is the evaluation of the subtle signs of hydrops fetalis. Even in the presence of a normal karyotype, perinatal outcome is very poor in the presence of fetal hydrops. Choroid plexus cyst (s) Vast majority of cyst (s) is benign and usually disappears by 24-25 weeks. However, these cysts may be associated with chromosomal anomalies, primarily trisomy 18 but occasionally trisomy 21. Choroid plexus cysts have been reported to be associated with trisomy 18 in 1% to 6 % cases. For isolated choroid plexus cysts, the risk for trisomy 18 and trisomy 21 is about 1.5 times the background. Intracardiac echogenic foci Increased echogenicity (golf ball) located in chordae tendinae is seen in 3 to 5 % of fetuses and is considered by most investigators of no pathological significance. However, they are sometimes associated with chromosomal abnormalities particularly, trisomy 21. For isolated hyperechogenic foci the risk for trisomy 21 may be four times the background. Hyperechogenic fetal bowel Hyperechogenic bowel has been described as a normal variant, but may also be associated with cystic fibrosis, meconium peritonitis, cytomegalovirus infection or trisomy 21. For isolated hyperechogenic bowel, the risk for trisomy 21 may be three times the background. Mild hydronephrosis Minimal pyelectasis in the fetus is common and unlikely to be significant in every case. However, UPJ obstruction and reflux may manifest initially as mild fetal pyelectasis. In addition, karyotype abnormalities, remarkably trisomy 21, are reported to be associated with mild pyelectasis. Long bone biometry Short humeri and short femurs may be found in fetuses with Down's syndrome. Measurements are usually compared with BPD rather than menstrual age due to the uncertainty of the menstrual history. If the femur length is below 5th centile and all other measurements are normal, the fetus is likely to be normal but rather short. However, this finding is rarely related to dwarfism and occasionally trisomy 21. Fetal hand Abnormalities of fetal hand such as polydactyly, over-riding fingers, or abnormal hand positioning, especially if associated with polyhydramnios, have been reported to be associated with fetal chromosomal abnormalities. Club foot / Rocker bottom feet (positional deformities) Club foot has been associated with a variety of chromosomal abnormalities, especially trisomy 13 and 18. Whether or not infants with isolated club foot are at significantly increased risk of chromosomal abnormalities is still unresolved. Rocker bottom feet are also a feature of trisomy 13 and 18. The finding of this deformity should be a stimulus to detailed fetal examination and fetal karyotyping. Single umbilical artery A single umbilical artery is found in 0.5% to 2% of newborns and is associated with structural or other anomalies in 20% to 50% of cases; usually relatively minor anomalies of the renal or genital tracts. Whether or not the presence of an isolated single umbilical artery is an indication for genetic studies is still uncertain. Intrauterine growth restriction A significant percentage of fetuses with chromosomal abnormalities are growth restricted. Some investigators have suggested the presence of IUGR alone is an indication for genetic studies. Many additional abnormalities such as cerebellar hypoplasia, isolated pericardial effusion, sandal-foot, reduction defect of forearm, low set ears or shortened ear length, fetal cholecystomegaly, and polyhydramnios have been found to be associated with chromosomal anomalies. When these findings are seen in isolation, it is still controversial whether or not amniocentesis should be offered. The sensitivity of ultrasonography for detection of fetal trisomic conditions varies with the type of chromosome abnormality, gestational age at the time of sonography, reasons for referral, criteria for positive sonographic findings, and the quality of the sonography. As an estimate, 1 or more sonographic findings can be identified in approximately 90% of fetuses with trisomy 13, 80% of fetuses with trisomy 18, and 50 % to 70% of fetuses with trisomy 21. Clusters of minor sonographic markers greatly increase the likelihood of karyotypic abnormality compared with a single minor marker . Cardiovascular anomalies Since malformations of the heart are the most common birth defect in fetuses with serious chromosomal abnormalities, color Doppler ultrasound evaluation of the cardiovascular system can be used to improve the detection rate of these abnormalities. By the inclusion of color Doppler sonography in genetic ultrasound, 96% of fetuses with Down's syndrome, 98% of all trisomies, and 88 % of all chromosomal abnormalities can be detected . A complete normal ultrasound examination result reduces the risk of abnormal karyotype,by,62%.
2.Biochemical,tests
A large number of serum analytes have been found to be associated with chromosomal abnormalities. Various principal biochemical analytes currently available for the prenatal screening of chromosomal abnormalities during first and second-trimester of pregnancy are; pregnancy associated plasma protein-A (PAPP-A), maternal serum alpha-feto-protein (MSAFP), free-beta hCG, total hCG, unconjugated estriol (uE3), and inhibin-A. PAPP-A and free-beta hCG are only biochemical markers identified to be of value in first-trimester screening. Free-beta hCG is the only marker that is effective in both the first and second-trimester pregnancy. PAPP-A It is a homotetrameric glycoprotein (metzincins family of metalloproteases) which is synthesized in chorionic villi . It can be measured in maternal serum; its concentration increases rapidly after 7th week of pregnancy and its potential clinical usefulness is greatest in the first trimester (10th to 14th week of gestation). When the fetus is affected with trisomy 21, PAPP-A levels are decreased by more than half . Low PAPP-A is also associated with trisomy 18 and 13. Using PAPP-A alone, detection rate of Down's syndrome is about 40%. When PAPP-A was combined with maternal age, the detection rate increased to 50% with a 5% screen-positive rate. Decreased production of PAPP-A may cause intrauterine growth restriction as this hormone control the level of insulin -like growth factors (IGF) in the placenta. MSAFP MSAFP is a glycoprotein produced by the fetal yolk sac and fetal liver. Fetal plasma concentration increases to a maximum (approximately 3.0-4.0 g/L) between 13-14 weeks of gestation. Maternal serum levels peak at about 30 weeks (about 250 mg/L).
High MSAFP levels may occur in the following conditions:
1. Underestimated gestational age 2. Multiple gestation. 3. Neural tube defects (anencephaly, spina bifida, encephalocele). 3 Abdominal wall defects (omphalocele, gastroschisis) 4. Various other fetal abnormalities such as hydrocephaly, microcephaly, cystic hygroma, cyclopia, tetralogy of Fallot, duodenal atresia, congenital nephropathies, sacrococcygeal teratoma, hydrops fetalis and Turner's syndrome without hygroma. 5. Complications of pregnancy ( fetal distress, growth retardation, early intrauterine death, placental defects, abdominal pregnancy, and maternal proteinuric preeclampsia). 6. Congenital fetal neoplasms, and maternal AFP producing neoplasms.
Low MSAFP levels may be associated with:
1. Incorrect pregnancy dating (less advanced than originally thought). 2. Complications of pregnancy (missed abortion, spontaneous abortion, late fetal death, molar pregnancy, choriocarcinoma). 3. Some normal pregnancies. 4. Large-for-dates. Very low MSAFP predicts an unusually high rate of large birth weight infants, with increased fetal, intrapartum, and neonatal consequenses. 5. MSAFP less than the median may indicate an increased risk of chromosomal abnormalities such as trisomy 21 and trisomy 18. The level of MSAFP in Down's syndrome pregnancies are about 72% of the normal values for weeks 14 to 21. Using maternal age and MSAFP level, the detection rate of Down's syndrome pregnancies is about 25-33%, at a false positive rate of 5% . Total hCG hCG is a dimeric glycoprotein composed of two non-covalently linked polypeptide sub-units, alpha and beta. It is first secreted by the fertilized ovum and later by placental tissue. Serum hCG levels increase exponentially between 3-10 weeks of pregnancy. Levels reach a peak during the first-trimester (about 100000 m IU/ml) and decline during the second and third-trimesters. In normal second-trimester maternal sera, the level of intact hCG ranges from 20,000-50,000 mIU/ml. In trisomy 21 pregnancies, second -trimester hCG levels are elevated varying from 2.04 to 2.5 MoM or greater while in trisomy 18 and 13, hCG levels are lower than normal. Using maternal age and hCG levels, Down's syndrome detection rate is about 60 % at a false positive rate of 6.7 % . Very high levels of hCG suggest trophoblastic disease. Various workers found a significant increase in the levels of free beta-hCG in trisomy 21, and concluded that this biochemical analyte is superior to intact hCG for the detection of trisomy 21. The levels of this analyte are reduced in the blood of women carrying fetuses with trisomy 18 . Unconjugated estriol (uE3) The substrate for estriol begins as dehydroepiandrosterone (DHEA) made by the fetal adrenal glands. This is later hydroxylated in fetal liver and cleaved by steroid sulphatase in placenta where unconjugated fraction converts to uE3. The amount of estriol in maternal serum is dependent upon a viable fetus, a properly functioning placenta, and maternal wellbeing. In normal pregnancies, uE3 levels increase from about 4 nmol/L at 15 weeks gestation to about 40 nmol/L at delivery. uE3 tends to be lower when trisomy 21or 18 is present and when there is adrenal hypoplasia with anencephaly. Second-trimester maternal serum uE3 levels in Down's syndrome pregnancies are approximated 75% of the values expected in normal pregnancies . Using maternal age and uE3 levels detection rate of about 45.7% at a false positive rate of 9.1 % was found . Inhibin-A Inhibin-A is a heterodimeric glycoprotein of placental origin similar to hCG. Inhibin-A levels in maternal serum are relatively constant through the 15th-18th week of pregnancy. Maternal serum levels of inhibin-A are twice as high in pregnancies affected by Down's syndrome as in unaffected pregnancies while in trisomy 18, inhibin-A levels are lower than normal. Inhibin-A is used with three other analytes (MSAFP, hCG, uE3) and maternal age to characterize more accurately Down's syndrome risk, and a reduction of the false positive rate was detected. Currently available evidences suggest that sensitivity of individual maternal serum markers is substantially low. To improve the sensitivity and specificity of biochemical markers, various combinations of 2, 3, or 4 analytes are offered during first and / or second-trimester screening.
Various combinations of analytes include;
1. First-trimester maternal serum double test using PAPP-A and free-beta hCG. This is vastly more effective than any other screening program and is of great advantage because it is available in the first-trimester. The disadvantage is that the test will not detect neural tube defects, so a MSAFP test will still need to be done. After combining PAPP-A and free beta-hCG with maternal age, detection rate of aneuploidy is about 60% at a 5% screen-positive rate.
2. Second-trimester screening includes; double test (MSAFP+ free-beta hCG or total hCG), triple test (MSAFP+hCG+uE3), and quad screen test (MSAFP+hCG+uE3+inhibin-A). When an ultrasound scan is used to estimate gestational age the Down's syndrome detection rate for a 5% false positive rate is estimated to be 59% using the double test (AFP and hCG), 69% using the triple test (AFP,hCG,uE3), and 76% using the quad test (AFP,hCG,uE3, inhibin-A), all in combination with maternal age. Main disadvantage of second-trimester screening is the timing of the test. By the time a definitive diagnosis is made via amniocentesis (after a positive screen result), the option of termination of pregnancy can be difficult. MSAFP is always included as a component of second-trimester biochemical screening because this analyte is widely used for the detection of ONTDs at this stage of pregnancy. Addition of uE3 as an analyte for prenatal screening is controversial. Some authors pointed out that inclusion of this analyte does not improve detection rates, where as in another study a fall in detection rate was noticed. On the other hand, some workers rely on the usefulness of uE3 as a serum marker. In a study, it was found that double test is not worse than the triple test and the double test is preferred because of lower running cost. Comparing free beta-hCG and total hCG, it was found that free beta hCG is better option because it improves the Down's syndrome detection efficiency by 10 % over total hCG at a lower false positive rate. Review of the literature suggests that the combined use of free beta-hCG and AFP instead of total hCG, AFP and uE3, is better screening test because it is more effective, less expensive, and is not limited to 16-20 weeks gestation. The addition of uE3 and inhibin-A adds no significant advantage to the double test. However, some workers recommend triple test while some rely on quad test for better results. Combined screening Since maternal biochemical and sonographic markers are largely independent, combined risk estimate results in even higher detection rate than either alone. Thus combination of a multiple marker test (PAPP-A and free b-hCG) and an ultrasound at 11 to 14 weeks which is targeted to look NT, and maternal age gives a detectable rate of aneuploidy of about 90 % with an invasive testing rate of about 5%. But in many high-risk situations this may still leave the patient at risk. Integrated screening The integrated test includes measurements of PAPP-A and NT in the first-trimester and measurements of MSAFP, uE3, hCG, and inhibin-A in the second-trimester. The integrated test can achieve a high detection rate with a much lower false positive rate (0.9%) than screening based on markers measured in either trimester alone. Consequently the need for amniocentesis or CVS is reduced by four fifths, with a similar reduction in the loss of unaffected fetuses. The estimates of the integrated test's performance are based on there being little or no correlation between the first and second-trimester markers used with the exception of free beta-hCG and total hCG. Disadvantage of the test is that it is expensive, and option of making the diagnosis in the first-trimester is eliminated.
Conclusions of multiple marker screening test:
1. Maternal blood screening is originally developed for pregnant women who are at a 'low-risk' for disorders being screened. However, in certain situations maternal serum marker screening can be assayed in women > or =35 years..
2. Gestational age must be accurately known. First-trimester screening is offered between 10 to 14 weeks of gestation, while second-trimester screening tests are given between 14 and 22 weeks of pregnancy, with 16 to 18 weeks (when the hormone levels are most consistent) being the optimum time.
3. Multiple gestation screening is not as sensitive as singleton screening with biochemical analysis.
4. Screening utilizing biochemical test, NT and maternal age mainly identifies aneuploidy and some other chromosomal abnormalities only and therefore shall miss majority of other non-Down, non-trisomy 18 chromosome abnormalities, nor does it identify other physical or mental birth defects.
5. A low PAPP-A, low MSAFP, low uE3, and high free beta-hCG, and high inhibin-A levels are associated with higher risk for Down's syndrome while low levels of all hormones suggest an increased risk for trisomy 18. In trisomy 13, PAPP-A and free beta-hCG levels are low but detection rate using second-trimester analytes is poor. Although screening protocol has a 90 % pickup rate of aneuploidy, it is not diagnostic. Hence, suspicious screening results will tell of an increased risk of a problem, but not diagnose the problem as being present or being absent.
3. Non-invasive screening using fetal blood cells and fetal DNA.
(a)Fetal blood cells:
The fetal and maternal circulations are separated by the placental membranes, but this barrier is incomplete to cellular trafficking. Bi-directionality and bimodality (cell and cell-free DNA) of fetomaternal trafficking is an established fact. Fetal nucleated cells such as trophoblasts, erythrocytes and white blood cells are found in maternal blood, and have been widely pursued as potential substrates for noninvasive prenatal diagnosis. However, concentration of these cells in maternal blood is very low and therefore isolation of these cells for cytogenetic analysis requires expensive euipments and great expertise. Isolation of erythroblasts has attracted most attention because they are abundant in early fetal blood, they are extremely rare in normal adult blood and their half-life in adult blood is only about 30 days. Relatively specific monoclonal anibodies against these cells are also available. Trophoblastic cells and white cells are not used for prenatal screening because trophoblastic cells are cleared by maternal lungs whereas half life of the white cells is very long which may lead to contamination from previous pregnancies. A combination of sophisticated physical and immunological methods are used for the identification, isolation and enrichment of different types of fetal blood cells from maternal blood obtained at 12-16 weeks of gestation. Physical methods include triple density gradient centrifugation and micromanipulation techniques while immunological methods include the use of magnetically labelled or fluorescent monoclonal antibodies such as anti-CD71 (transfferin receptor). Commonly used immunological methods are, magnetic cell sorting (MACS) or fluorescence activated cell sorting (FACS). By these methods the fetal cells can be enriched to about 1 in 10-100 materanl cells. Enriched cells are used for the detection of specific chromosomes by fluorescent in situ hybridization (FISH) and for the analysis of fetal genetic loci by single cell PCR. FISH involves the hybridization of DNA probes representing a specific chromosome or chromosomal region to target DNA such as metaphase chromosomes or interphase nuclei. Fetal trisomy is suspected if some of the enriched cells show three-signal nuclei rather than the normal two.
Over the past decade, progress has been made towards the isolation and analysis of fetal blood cells from maternal blood, using various enrichment strategies and analysis by fluorescent in situ hybridization with choromosome-specific probes and PCR. It is now possible to identify simultaneously all major chromosomal abnormalities by the use of multi color probes directed against chromosomes 21,18,13,Y and X in interphase nuclei. Another method that is currently being explored involves culturing fetal blood cells. The sensitivity for detecting aneuploidy using fetal cells is competitive with first or second-trimester maternal serum screening with the advantage that the invasive testing rate may be as low as 0% rather than 5%. But the current technology precludes application of this concept for mass population. However, fetal cells might be analyzed only after a positive serum or ultrasound finding. If fetal aneuploid cells are not recovered, an invasive diagnostic procedure could be avoided.
(b) Fetal DNA Isolation of fetal cells
from the cellular fraction of maternal blood needs expensive and advance equipment because of the rarity of such cells. Recently, there has been much interest in the use of the non-cellular portion of blood, namely plasma, for molecular analysis diagnosis. Fetal DNA has been identified in the plasma of pregnant women at concentrations much higher than those present in the cellular fraction. Until recently, it was assumed that fetal DNA detected in maternal plasma was cell free and a definitive diagnosis of fetal chromosomal aneuploidies was not thought possible. Studies now indicate that some fetal DNA originates from intact fetal cells. Trophoblasts may be the predominant cell population involved in the liberation of fetal DNA into the cell-free fraction. It was found that the absolute concentration of fetal DNA in maternal serum increases with gestational age, with a sharp rise near the end of the pregnancy. Fetal DNA is cleared rapidly from maternal blood after delivery with a half-life of minutes. Increase in fetal DNA in maternal plasma has been noticed in pregnancies affected by fetal trisomy, and in premature labour, and preeclampsia. Using fetal DNA in maternal plasma for the screening of fetal chromosome aneuploidies is possible, especially in conjugation with other established serum markers. The median fetal DNA concentration in Down's syndrome cases was found to be 1.7 times higher than in controls. Second-trimester cell-free fetal DNA estimation gave a 21% detection rate at a 5% false-positive rate. When added to quadruple marker screening, fetal DNA estimation modestly increased the screening performance above what is currently available in the second-trimester. The relative ease and reliability with which fetal DNA can be detected have thus opened new possibilities for non-invasive prenatal diagnosis.
Invasive diagnostic procedures
1.Chorionic villus sampling CVS is a prenatal test that involves taking a sample of some of the placental tissue. Main complications of CVS include severe transverse limb defects and oromandibular-limb hypogenesis. Possible mechanism of severe transverse limb abnormalities is hypoperfusion, embolization and release of vasoactive substances due to trauma during the procedure. There is strong association between the severity of the defect and the gestation at sampling. Decreasing risk and a trend from proximal to distal limb damage with increasing gestational age at CVS provide biologic plausibility for a true association with limb reduction defects . CVS as early as 8 weeks of gestation may lead to amputation of whole limb while sampling at 10 weeks only affects terminal phalanxes. Thus, to avoid severe limb defects, CVS prior to 11 weeks of gestation should be discouraged. The increase in the miscarriage rate following this procedure is about 0.5% above the background risk for miscarriage, which is 2-3% at 10-12 weeks of pregnancy. Various trials compared CVS in first-trimester and amniocentesis in the second-trimester and concluded that both procedures are equally effective and safe with similar rates of procedure-induced fetal loss at experienced centers. The main advantage of CVS over amniocentesis is that prenatal diagnosis is achieved during the first-trimester, which allows a couple the opportunities to consider their options earlier in the pregnancy in the event of an abnormal result. However, screening for ONTDs cannot be achieved through CVS. The main indication for repeat CVS is mosaicism.
2.Amniocentesis
Amniocentesis was first used for prenatal diagnosis in the 1950's and the feasibility of culturing and karyotyping amniotic fluid cells was first demonstrated in the late 1960s. Although the exact risk associated with amniocentesis is controversial, it is also not a completely innocuous procedure and can result in various complications such as spontaneous abortion, premature labour, placental abruption, intrauterine death and neonatal death.
Other reported procedure-related complications include increased risk of respiratory distress syndrome and pneumonia in neonates, talipes and dislocation of the hip, postprocedural amniotic fluid leakage of amniotic fluid, vaginal bleeding, chorioamnionitis, amniotic band formation and rare needle puncture of the fetus.
Amniocentesis may results in future reproductive complications secondary to sensitization to Rh and other rare antigens such as Kell. Amniocentesis can be performed as early as 11-13 weeks of gestation. But at this stage of pregnancy, the procedure is not only technically difficult to perform, it is also associated with increased incidence of total fetal loss, talipes equinovarus and post-procedural amniotic fluid leakage. Incidence of failed culture is also high in early amniocentesis. Thus, the procedure should not be performed before 13 weeks gestation unless there are special circumstances.
Potential advantage associated with amniocentesis includes; 1.The amniotic fluid can be tested to measure the amount of AFP, which is a diagnostic test for detecting ONTDs 2. Possibility of an abnormal chromosome result due to chromosomal mosaicism confined to the placenta is reduced.
