Prenatal diagnosis

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Prenatal testing is testing for diseases or conditions in a fetus or embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate, Tay Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, and fragile x syndrome. Screening can also determine the sex of the fetus. Common testing procedures include amniocentesis, sonograms, nuchal translucency ultrasound, serum marker testing, or genetic screening. In some cases, the tests are administered to determine if the fetus will be aborted, though physicians and patients also find it useful to diagnose high-risk pregnancies early so that delivery can be scheduled in a tertiary care hospital where the baby can receive appropriate care.

Diagnostic prenatal testing can be by invasive or non-invasive methods. An invasive method involves probes or needles being inserted into the placenta, e.g. amniocentesis, which can be done from about 14 weeks gestation, and usually up to about 20 weeks, and chorionic villus sampling, which can be done earlier (between 9.5 and 12.5 weeks gestation) but which is slightly more risky to the fetus. Non-invasive methods, called "screens", can only evaluate risk of a condition and cannot determine 100% if the fetus has a condition. Non-invasive techniques include examinations of the woman's womb through ultrasonography and maternal serum screens (i.e. Alpha-fetoprotein). Non-invasive genetic tests for Down Syndrome, Trisomy 18, and Trisomy 13 fetal DNA present in maternal blood are in development.^[1] If an elevated risk of chromosomal or genetic abnormality is indicated by a non-invasive screening test, a more invasive technique may be employed to gather more information. In the case of neural tube defects, a detailed ultrasound can non-invasively provide a definitive diagnosis.

Fetal screening has also been done to determine characteristics generally not considered birth defects. In some parts of the world, if a fetus is determined to be female, it is sometimes aborted. The rise of designer babies and parental selection for specific traits raises a host of bioethical and legal issues that will dominate reproductive rights debates in the 21st century.

[edit] Fetal versus maternal

Some screening tests performed on the woman are intended to detect traits or characteristics of the fetus. Others detect conditions in the woman that may have an adverse effect on the fetus, or that threaten the pregnancy. For example, abnormally low levels of the serum marker PAPP-A have been shown to correspond to an increased risk of pre-eclampsia, in which the mother's high blood pressure can threaten the pregnancy, though many physicians find regular blood-pressure monitoring to be more reliable.

[edit] Reasons for prenatal diagnosis

There are three purposes of prenatal diagnosis: (1) to enable timely medical or surgical treatment of a condition before or after birth, (2) to give the parents the chance to abort a fetus with the diagnosed condition, and (3) to give parents the chance to "prepare" psycologically, socially, financially, and medically for a baby with a health problem or disability, or for the likelihood of a stillbirth.

Having this information in advance of the birth means that healthcare staff can better prepare themselves and parents for the delivery of a child with a health problem. For example, Down Syndrome is associated with cardiac defects that may need intervention immediately upon birth

Many expectant parents would like to know the sex of their baby before birth. Methods include amniocentesis with karyotyping, and prenatal ultrasound. In some countries, health care providers are expected to withhold this information from parents, while in other countries they are expected to give this information.^{[citation needed]}

[edit] Methods of prenatal screening and diagnosis

[edit] Non-invasive methods

Examination of the woman's uterus from outside the body.
Ultrasound detection - Commonly dating scans (sometimes known as booking scans) from 7 weeks to confirm pregnancy dates and look for twins. The specialised nuchal scan at 11-13 weeks may be used to identify higher risks of Downs syndrome. Later morphology scans from 18 weeks may check for any abnormal development.
Listening to the fetal heartbeat (see stethoscope)
External fetal monitoring, often known as a non-stress test

[edit] Less invasive methods

Second trimester maternal serum screening (AFP screening, triple screen, quad screen, or penta screen) can check levels of alpha fetoprotein, β-hCG, inhibin-A, estriol, and h-hCG (hyperglycosolated hCG) in the woman's serum.
First trimester maternal serum screening can check levels of free β-hCG, PAPP-A, intact or beta hCG, inhibin-A, or h-hCG in the woman's serum, and combine these with the measurement of nuchal translucency (NT). Some institutions also look for the presence of a fetal nasalbone on the ultrasound.
Integrated, Sequential, and Contingent screening tests use serum samples from both first and second trimester, as well as the nuchal translucency measurement to calculate risks. With Integrated screening, a report is only produced after both samples have been analyzed. With Sequential screening, a first report is produced after the first trimester sample has been submitted, and a final report after the second sample. With Contingent screening, patients at very high or very low risks will get reports after the first trimester sample has been submitted. Only patients with moderate risk will be asked to submit a second trimester sample, after which they will receive a report combining information from both serum samples and the NT measurement.
Detection of fetal blood cells in maternal blood. With this technique, it is technically possible to obtain a sample of fetal DNA using blood cells from the fetus that have made their way into the woman's bloodstream. Tests such as Baby Gender Mentor allegedly use this method to determine the sex of a fetus as early as six weeks into a pregnancy. However, fetal blood cells in maternal blood are extremely rare and very fragile, making it very hard to handle and analyze them. Several companies continue to develop technologies that may someday offer a new way to screen or even diagnose chromosomal abnormalities.

[edit] More invasive methods

Chorionic villus sampling - Involves getting a sample of the chorionic villus and testing it. This can be done earlier than amniocentesis, but may have a higher risk of miscarriage, estimated at 1%.
Amniocentesis - This can be done once enough amniotic fluid has developed to sample. Cells from the fetus will be floating in this fluid, and can be separated and tested. Miscarriage risk of amniocentesis is commonly quoted as 0.5% (1:200).
Embroscopy and fetoscopy - Though rarely done, these involve putting a probe into a women's uterus to observe (with a video camera), or to sample blood or tissue from the embryo or fetus.

[edit] Risk factors qualifying a pregnant woman for prenatal testing

Because of the miscarriage and fetal damage risks associated with amniocentesis and CVS procedures, many women prefer to first undergo screening so they can find out if the fetus' risk of birth defects is high enough to justify the risks of invasive testing. Since screening tests yield a risk score which represents the chance that the baby has the birth defect, the most common threshold for high-risk is 1:270. A risk score of 1:300 would therefore be considered low-risk by many physicians. However, the trade-off between risk of birth defect and risk of complications from invasive testing is relative and subjective; some parents may decide that even a 1:1000 risk of birth defects warrants an invasive test while others wouldn't opt for an invasive test even if they had a 1:10 risk score.

ACOG guidelines current recommend that all pregnant women, regardless of age, be offered invasive testing to obtain a definitive diagnosis of certain birth defects. Therefore, most physicians offer diagnostic testing to all their patients, with or without prior screening and let the patient decide.

The following are some reasons why a patient might consider her risk of birth defects already to be high enough to warrant skipping screening and going straight for invasive testing.

Women over the age of 35
Women who have previously had premature babies or babies with a birth defect, especially heart or genetic problems
Women who have high blood pressure, lupus, diabetes, asthma, or epilepsy
Women who have family histories or ethnic backgrounds prone to genetic disorders, or whose partners have these
Women who are pregnant with multiples (twins or more)
Women who have previously had miscarriages

[edit] Typical screening sequence

California provides a useful guide to most of the currently available screening paradigms. ^[2]

At early presentation of pregnancy at around 6 weeks, and early dating ultrasound scan may be offered to help confirm the gestational age of the embryo, and check whether a single or twin pregnancy, but such a scan is unable detect common abnormalities. Details of prenatal screening and testing options may be provided.

Around weeks 10-11, nuchal thickness scan (NT) may be offered which can be combined with blood tests for PAPP-A and beta-hCG, two serum markers that correlate with chromosomal abnormalities, in what is called the First Trimester Combined Test. The results of the blood test are them combined with the NT ultrasound measurements, maternal age, and gestational age of the fetus to yield a risk score for Down Syndrome, Trisomy 18, and Trisomy 13. First Trimester Combined Test has a sensitivity (i.e. detection rate for abnormalities) of 82-87% and a false-positive rate around 5%.

Altenatively a second trimester Quad blood test may be taken (the triple test is widely considered obsolete but in some states, such as Missouri, where Medicaid only covers the Triple test, that's what the patient typically gets). Performing this in addition to the First Trimester Combined Test is called the Fully Integrated test, which has a sensitivity of 95% with a 5% false-positive rate, though can also be analyzed in such a way as to offer a 90% sensitivity with a 2% false-positive rate. However patients may not wish to wait between these two sets of test.

If First Trimester Combined test suggests an unacceptably high risk of chromosomal abnormalities may be confirmed with invasive procedures of chorionic villus sampling (CVS) available from 9 weeks, or the second trimester amniocentesis, which is considered to have a lower risk of miscarriage than CVS. Whereas those who receive a low-risk score may consider further unnecessary. Care programs that offer 2nd trimester Quad tests to those with medium risks (lower than 1:50) are termed a Sequential test, and if only to those with an intermediate risk score (between 1:50 and 1:2000) from the 1st Trimester Combined test (with lower risk patients skipping the Quad test and higher risk patients going for invasive testing) are termed a Contingent Screen with an 88-94% sensitivity and 5% false-positive rate for Down Syndrome.

Finally for patients who do not receive an NT ultrasound in the 1st trimester may still receive a Serum Integrated test involving measuring PAPP-A serum levels in the 1st trimester and then doing a Quad test in the 2nd trimester. This offers an 85-88% sensitivity and 5% false-positive rate for Down Syndrome. Also, patient may skip 1st trimester screening entirely and receive only a 2nd trimester Quad test, with an 81% sensitivity for Down Syndrome and 5% false-positive rate.

Use of NT ultrasound will screen for Down Syndrome (Trisomy 21), Edwards Syndrome (Trisomy 18), and Patau Syndrome (Trisomy 13), whilst screens that only use serum markers will screen for Down Syndrome and Trisomy 18, but not Trisomy 13. Considering that Trisomy 13 is extremely rare, maybe 1:5000 pregnancies and 1:16000 births, this difference is probably not significant. The AFP marker, whether alone or as part of the Quad test, can identify 80% of spina bifida, 85% of abdominal wall defects, and 97% of anencephaly. Frequently women will receive a detailed 2nd trimester ultrasound in Weeks 18-20 (Morphology scan) regardless of her AFP level, which makes the AFP score unnecessary. Morphology ultrasound scans being undertaken on larger sized fetuses than in earlier scans, detect other structural abnormalities such as cardiac and renal tract abnormailities.

[edit] Rarer conditions also detected

In addition to the direct seeking of chromosomal abnormalities and spina bifida, the blood tests can suggest additional conditions:

Very low estriol level (part of Quad test) can indicate a risk of Smith-Lemli-Opitz Syndrome (SLOS), an extremely rare (1:100,000) genetic disorder which can then only be confirmed with an amniocentesis. However with a 0.3% false-positive rate, 300 women would be told they are at high-risk of SLOS for every 1 affected pregnancy. Most physicians would agree that subjecting 300 women to an amniocentesis to diagnose 1 case of SLOS is not prudent.
A low PAPP-A reading from a 1st Trimester serum test could also indicate a risk for pre-eclampsia, intra-uterine growth restriction (IUGR), or early fetal demise (i.e. miscarriage). However, because PAPP-A only weakly correlates with these conditions and, in any case, there's little that one can do about them (except for pre-eclampsia, though that is better identified by other means), a PAPP-A test makes little sense except as a component of Down Syndrome screening.

[edit] Ethical and practical issues

[edit] Ethical issues of prenatal testing

The option to continuing or aborting a pregnancy is the primary choice after most prenatal testing. Rarely, fetal intervention corrective procedures are possible.
Are the risks of prenatal diagnosis, such as amniocentesis worth the potential benefit?
Some fear that this may lead to being able to pick and choose what children parents would like to have. This could lead to choice in sex, physical characteristics, and personality in children. Some feel this type of eugenic abortion is already underway (sex-selective, etc.)
Knowing about certain birth defects such as spina bifida and teratoma before birth may give the option of fetal surgery during pregnancy, or assure that the appropriate treatment and/or surgery be provided immediately after birth.
Questions of the value of mentally or physically disabled people in society
How to ensure that information about testing options is given in a non-directive and supportive way.
That parents are well informed if they have to consider abortion vs. continuing a pregnancy. See wrongful abortion.

[edit] Will the result of the test affect treatment of the fetus?

In some genetic conditions, for instance cystic fibrosis, an abnormality can only be detected if DNA is obtained from the fetus. Usually an invasive method is needed to do this.

If a genetic disease is detected, there is often no treatment that can help the fetus until it is born. This does give parents the option to consider abortion.

If abortion isn't an option for a particular couple (because of their own beliefs or the laws of their country), invasive prenatal diagnosis of such a condition is unhelpful as the test puts the fetus at risk, and knowing the result doesn't help the fetus. Genetic counseling can help families make informed decisions regarding results of prenatal diagnosis.

[edit] False positives and false negatives

Ultrasound of a fetus, which is considered a screening test, can sometimes miss subtle abnormalities. For example, studies show that a detailed 2nd trimester ultrasound, also called a level 2 ultrasound, can detect about 97% of neural tube defects such as spina bifida. Ultrasound results may also show "soft signs," such as an Echogenic intracardiac focus or a Choroid plexus cyst, which are usually normal, but can be associated with an increased risk for chromosome abnormalities.

Other screening tests, such as the Quad test, can also have false positives and false negatives. Even when the Quad results are positive (or, to be more precise, when the Quad test yields a score that shows at least a 1 in 270 risk of abnormality), usually the pregnancy is normal, but additional diagnostic tests are offered. In fact, consider that Down Syndrome affects about 1:400 pregnancies; if you screened 4000 pregnancies with a Quad test, there would probably be 10 Down Syndrome pregnancies of which the Quad test, with its 80% sensitivity, would call 8 of them high-risk and about 5% or 200 of the 3990 normal women that they are high-risk. Therefore, about 208 women would be told they are high-risk, but when they undergo an invasive test, only 8 (or 4%) will be confirmed as positive and 200 (96%) will be told that their pregnancies are normal. Since amniocentesis has approximately a 0.5% chance of miscarriage, one of those 200 normal pregnancies might result in miscarried because of the invasive procedure. Meanwhile, of the 3792 women told they are low-risk by the Quad test, 2 of them will go on to deliver a baby with Down Syndrome. The Quad test is therefore said to have a 4% positive predictive value (PPV) because only 4% of women who are told they are "high-risk" by the screening test actually have an affected fetus. The other 96% of the women who are told they are "high-risk" suffer anxiety because the screening test was wrong, at least until they get the results back from their invasive procedure and find out their pregnancy is normal.

By comparison, in the same 4000 women, a screening test that has a 99% sensitivity and 0.5% false positive rate, would detect all 10 positives while telling 20 normal women that they are positive. Therefore, 30 women would undergo a confirmatory invasive procedure and 10 of them (33%) would be confirmed as positive and 20 would be told that they have a normal pregnancy. Of the 3970 women told by the screen that they are negative, none of the women would have an affected pregnancy. Therefore, such a screen would have a 33% positive predictive value. It's still unfortunate that 20 false-positive women have had to undergo an invasive procedure to find out they have a normal pregnancy, but it's still better than 200 false-positives with the Quad test.

The real-world false-positive rate for the Quad test (as well as 1st Trimester Combined, Integrated, etc) is greater than 5%. 5% was the rate quoted in the large clinical studies that were done by the best researchers and physicians, where all the ultrasounds were done by well-trained sonographers and the gestational age of the fetus was calculated as closely as possible. In the real world, where calculating gestational age may be a less precise art, the formulas that generate a patient's risk score are not as accurate and the false-positive rate can be higher, even 10%.

Because of the low accuracy of conventional screening tests, 5-10% of women, after those who are older, will opt for an invasive test even if they received a low-risk score from the screening. A patient who received a 1:330 risk score, while technically low-risk (since the cutoff for high-risk is commonly quoted as 1:270) might be more likely to still opt for a confirmatory invasive test. On the other hand, a patient who receives a 1:1000 risk score is more likely to feel assuaged that her pregnancy is normal.

Both false positives and false negatives will have a large impact on a couple when they are told the result, or when the child is born. Diagnostic tests, such as amniocentesis, are considered to be very accurate for the defects they check for, though even these tests are not perfect, with a reported 0.2% error rate (often due to rare abnormalities such as mosaic Down Syndrome where only some of the fetal/placental cells carry the genetic abnormality).

A higher maternal serum AFP level indicates a greater risk for anencephaly and open spina bifida. This screening is 80% and 90% sensitive for spina bifida and anencephaly, respectively.^{[citation needed]}

Amniotic fluid acetylcholinesterase and AFP level are more sensitive and specific than AFP in predicting neural tube defects.

Many maternal-fetal specialists do not both to even do an AFP test on their patients because they do a detail ultrasound on all of them in the 2nd trimester, which has a 97% detection rate for neural tube defects such as anencephaly and open spina bifida.

No prenatal test can detect all forms of birth defects and abnormalities.

[edit] Societal Pressures on Prenatal Testing Decisions

Amniocentesis has become the standard of care for prenatal care visits for women who are "at risk" or over a certain age. All obstetricians offer patients the AFP triple test, HIV test, and ultrasounds routinely. However, almost all women meet with a genetic counselor before deciding whether to have prenatal diagnosis. It is the role of the genetic counselor to accurately inform women of the risks and benefits of prenatal diagnosis. Genetic counselors are trained to be non-directive and to support the patient's decision. Some doctors do advise women to have certain prenatal tests and the patient's partner may also influence the woman's decision.

[edit] Informed consent and medical malpractice

Obstetricians have an ethical duty to properly inform patients of their options, specifically the availability of screening and diagnostic testing. Physicians have been successfully sued by women who gave birth to babies with abnormalities that could have been detected had they known about their screening options, though the plaintiff must also prove that she would have elected to terminate the pregnancy in the event of a positive finding. Also, physicians who fail to inform their patients of the risks of amniocentesis and CVS might be found guilty of negligence informed consent in the event that the patient sues after a procedure-related miscarriage or fetal damage.

There is a misconception that a physician only needs to do what other physicians typically do (i.e. standard of care). However, in the case of informed consent, the legal standard is more commonly defined as what a reasonable patient would elect to do if she is informed. So if a reasonable patient would want to be screened if only she is informed or if a reasonable patient would want to receive an amniocentesis if only she is informed of that option, then a physician is legally obligated to inform the patient of these options.

As newer, more accurate screening tests emerge, physicians may need to quickly get up to speed on the most recent data and start informing their patients of the existence of these tests. Failure to inform patients of the available of these more accurate screening tests might result in a wrongful birth or wrongful miscarriage lawsuit if the patient can demonstrate that she would have chosen the newer test, if she had known about it, to avoid the unfortunate outcome that resulted from receiving a conventional screening test or invasive procedure.

[edit] See also

Genetic counseling

[edit] References

[edit] External links

First Trimester Screening for Downs Syndrome, National Research Center for Women & Families

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[1] ttp://www.cdph.ca.gov/programs/pns/Documents/Provider%20Handbook%20%202009%20WEB.pdf

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