There are currently several options available to pregnant women for the prenatal diagnosis of chromosomal abnormalities and for numerous single gene disorders.  These procedures are amniocentesis, early amniocentesis and chorionic villus sampling.  The availability of these techniques may be limited in your region, and testing options will change over time.  Thus, we would encourage an ongoing dialogue between primary health-care providers and regional genetics centers/prenatal diagnostic clinics regarding the availability of and risks associated with specific tests.  The decision whether or not to have prenatal testing, as well as which procedure to have, is often a very difficult one to make.  Visiting with a genetic counselor may assist your families in making an appropriate decision.

Chorionic villus sampling

Chorionic villus sampling (CVS) is the procedure currently available the earliest in pregnancy.  It is usually performed between 10 and 12 menstrual weeks gestation.  Consult with your regional genetics center regarding dating parameters and recommendations for prior dating ultrasounds or cervical cultures.  This procedure is performed either transvaginally using a catheter, or transabdominally using a needle.  The device is inserted into the developing placenta under ultrasound guidance and the villi are aspirated into the attached syringe.  The tissue is brought to the laboratory where the villi are dissected from the maternal decidua and either cultured for chromosomal analysis or processed further for DNA or biochemical analysis. From the mother's perspective, the transvaginal CVS feels very similar to a routine PAP smear, except for the full bladder necessary for better ultrasound visualization.  The aspiration is usually painless, however, the positioning (full bladder, speculum, and abdominal pressure from the ultrasound probe) is often uncomfortable. 

Transabdominal CVS feels similar to amniocentesis in that there may be discomfort and/or uterine cramping at the site of the needle insertion.  Common complications following CVS include mild cramping and vaginal spotting.  Most women feel well enough after CVS to resume normal activities.  However, as with the other procedures, they are advised to avoid strenuous activities for 24-48 hours and to seek medical care in the event of more serious complications. 

Potential risks involved with CVS include pregnancy complications which could result in miscarriage, an inability to provide conclusive results, and a possible increased risk for limb defects in the fetus.  Inconclusive results (e.g., chromosomal mosaicism) may necessitate a second procedure.  Precise risks may be site specific, and may vary among genetics centers.  The risk for procedure‑related pregnancy loss is slightly greater for CVS than amniocentesis.  However, the exact risks are more difficult to ascertain due to the higher background rate of pregnancy loss during the first trimester.  Several studies have reported a higher incidence of terminal transverse limb reduction defects (i.e., missing fingers and toes or portions thereof) following CVS, while other large-scale collaborative studies have disputed this association.  Although the magnitude of the risk is controversial, it is most likely <1% and probably <1/1000.  This risk may be higher when the procedure is performed before the 10th week, and may also be related to the specific device used for sampling and the size of the sample. 

Limitations include the inability to perform a high resolution ultrasound at the early gestational age when CVS is performed, and the inability to screen for neural tube defects.  Some cytogenetics laboratories report that chromosomes from CVS are usually too short to identify micro‑deletions or subtle chromosomal abnormalities.  Certain metabolic disorders are not expressed in villus cells, preventing prenatal diagnosis by CVS.

Benefits of CVS include the early gestational age at which the results are received, providing early reassurance or the ability to make decisions about terminating the pregnancy at a time when the decision can be more private; that DNA analysis for single gene disorders may be much faster and easier with CVS since the cells may not need to be cultured prior to analysis; and that specific metabolic disorders that are not expressed in amniocytes, preventing prenatal diagnosis by amniocentesis, can be diagnosed using CVS. 

Amniocentesis

Amniocentesis is usually performed at 15-16 weeks gestation by inserting a 22 gauge spinal needle into the amniotic sac.  This procedure is usually done under ultrasound guidance so that there is continuous visualization of the fetus and needle.  In terms of discomfort, the procedure is generally comparable to a blood draw; however, some women report uterine cramping, especially if the uterus contracts when the needle is in place.  Generally, women feel relieved following amniocentesis and resume their normal activities.  They are advised to avoid strenuous activity for 24-48 hours and to contact their care providers in the event of complications.

Still considered the “gold standard” for prenatal diagnosis in many ways, benefits of amniocentesis include a lower risk for significant pregnancy complications (<1/200), including miscarriage.  Amniocentesis also has the lowest risk for cell culture failure and fetal damage.  Amniotic fluid can be studied for neural tube and abdominal wall defects, infections, biochemical disorders, as well as chromosomal abnormalities.  Not only is the chromosome quality superior, but the amniocytes are more likely to be representative of the fetal karyotype. 

Limitations of amniocentesis include the relatively late gestational age at which the procedure is performed and results received.  Results may not be available until 18 weeks gestation when quickening often occurs.  At this time, the pregnancy is more obvious, making decision‑making more difficult and less private.  The concept of the procedure (i.e., a needle in the abdomen) can be very distressing to some women with needle anxiety.  It may also take longer for the results of DNA testing if cultured cells are needed for analysis. 

Early Amniocentesis

Early amniocentesis (EA) generally refers to any amniocentesis performed prior to 15 weeks gestation.  However, the gestational ages when it is performed may vary from center to center.  In some centers this procedure is performed from 10-14 weeks gestation; while other centers may only perform EA at 14 weeks gestation.  Each center may also have specific criteria for offering the procedure, such as evidence of chorioamniotic fusion, a posterior placenta, or absence of maternal obesity.  For these reasons, women who are scheduled for an early amniocentesis are more likely to be rescheduled for a later date than women who are scheduled for routine amniocentesis or CVS.  The procedure is identical to routine amniocentesis except that a smaller amount of fluid is extracted. 

Risks involved with early amniocentesis are still not clearly defined.  Published rates of pregnancy loss following EA range from <1% to 5.3%.  Some authors report losses comparable to routine amniocentesis, others report losses comparable to CVS, while others suggest a higher post-procedural loss rate than CVS or routine amniocentesis.  There may also be a higher rate of amniotic fluid leakage following EA.  Some studies have also suggested a higher than expected incidence of orthopedic and respiratory problems among children exposed to EA; and some earlier studies reported a higher incidence of cell culture failure, but this does not appear to be as prevalent as first reported.  Since a smaller quantity of fluid is extracted, it generally takes longer to receive test results because fewer cells are present to initiate the cell culture. 

Limitations include the absence of norms for amniotic fluid alpha-fetoprotein medians at early gestational ages, so that neural tube defects may not be identifiable.  A few enzyme‑based metabolic disorders may also lack values for comparison at early gestational ages. Benefits of EA are similar to the benefits of CVS.  The early gestational age at which the results are received enables early reassurance, or early decision-making.  The quality of the chromosome study is comparable to routine amniocentesis, making it less likely that a small chromosome deletion would be missed. 

Conclusion

The choice of which test, if any, is often very difficult and is influenced by the couple's feelings about the pregnancy, their feelings about the information which can be provided through testing, the sorts of options which they feel are appropriate, and their moral, ethical and religious beliefs.  No prenatal test can guarantee a healthy child and there are no cures available for the vast majority of conditions for which testing is possible.  Although structural defects, such as renal agenesis, may not be apparent on ultrasound when early testing is performed, many conditions can be identified later in the second trimester by detailed ultrasonography in conjunction with maternal serum alpha fetoprotein screening. 

References
1)  Bissonnette JM, Busch WL, Buckmaster JG, Olson SB, Nesler CL (1993).  Factors associated with limb anomalies after chorionic villus sampling.  Prenat Diagn 13:1163-1165.
2)  Burton BK, Schulz CJ, Burd LI (1992).  Limb anomalies associated with chorionic villus sampling.  Obstet Gynecol 70:726-730.
3)  Canadian Collaborative CVS-Amniocentesis Clinical Trial Group (1989).  Multicentre randomized clinical trial of chorion villus sampling and amniocentesis.  Lancet i, 1-6.
4)  Crandall BF, Kulch P, Tabsh K (1994).  Risk assessment of amniocentesis between 11 and 15 weeks: comparison to later amniocentesis controls.  Prenat Diagn 14:913-919.
5)  Firth HV, Boyd PA, Chamberlain P, MacKenie IZ, Lindenbaum RH Huson, SM (1991).  Severe limb abnormalities after chorion villous sampling at 56‑66 days gestation.  Lancet 337:762-763.
6)  Nicolaides K, de Lourdes Brizot M, Patel F, Snijders R (1994).  Comparison of chorionic villus sampling and amniocentesis for fetal karyotyping at 10-13 weeks gestation. Lancet 344:435-439.
7)  Shulman LP, Elias S, Phillips OP, Grevengood C, Dungan JS, Simpson JL (1994).  Amniocentesis performed at 14 weeks gestation or earlier:  comparison with first-trimester transabdominal chorionic villus sampling.  Obstet Gynecol 83:543-548.

(Last Updated 5/23/01)
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