Fetal screening has also been done to determine characteristics generally not considered birth defects, and avail for e.g. sex selection. 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.
Invasiveness
Diagnostic prenatal testing can be by invasive or non-invasive methods. An invasive method involves probes or needles being inserted into the uterus, 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 may be slightly more risky to the fetus. However since chorionic villus sampling is performed earlier in the pregnancy than amniocentesis, typically during the first trimester, it can reasonably be expected that there will be a higher rate of miscarriage after chorionic villus sampling than after amniocentesis. Non-invasive techniques include examinations of the woman's womb through ultrasonography and maternal serum screens (i.e. Alpha-fetoprotein) and also genetic analysis on fetal cells isolated from maternal blood. Non-invasive tests for Down Syndrome, Trisomy 18, and Trisomy 13 fetal DNA present in maternal blood are in development.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 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.
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" psychologically, 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 as well as parents can better prepare themselves 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.
Qualifying risk factors
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 currently 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
Methods of prenatal screening and diagnosis
There are multiple ways of classifying the methods available, including the invasiveness and the time performed.
Invasiveness Test Comments Time
Non-invasive Fetal Cells in Maternal Blood (FCMB) Based on enrichment of fetal cells which circulate in maternal blood. Since fetal cells hold all the genetic information of the developing fetus they can be used to perform prenatal diagnosis.[5] First trimester
Non-invasive Cell-free Fetal DNA in Maternal Blood Based on DNA of fetal cell origin circulating in the maternal blood. 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. Recent developments have also allowed such testing to be used to detect fetal aneuploidy. Fetal DNA ranges from about 2-10% First trimester
Non-invasive Preimplantation Genetic Diagnosis (PGD) During in vitro fertilization (IVF) procedures, it is possible to sample cells from human embryos prior the implantation. PGD is in itself non-invasive, but IVF usually involves invasive procedures such as transvaginal oocyte retrieval prior to implantation
Non-invasive External examination Examination of the woman's uterus from outside the body. First or second trimester
Non-invasive 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. First or second trimester
Non-invasive Fetal heartbeat Listening to the fetal heartbeat (see stethoscope) First or second trimester
Non-invasive Non-stress test Use of cardiotocography during the third trimester to monitor fetal wellbeing Third trimester
Less invasive Maternal serum screening (triple test) 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. Second trimester
Less invasive Transcervical retrieval of trophoblast cells Cervical mucus aspiration, cervical swabbing, and cervical or intrauterine lavage can be used to retrieve trophoblast cells for diagnostic purposes, including prenatal genetic analysis. Success rates for retrieving fetal trophoblast cells vary from 40% to 90%. It can be used for fetal sex determination and identify aneuploidies. Antibody markers have proven useful to select trophoblast cells for genetic analysis and to demonstrate that the abundance of recoverable trophoblast cells diminishes in abnormal gestations, such as in ectopic pregnancy or anembryonic gestation. First trimester
Less invasive Maternal serum screening (triple test) 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. First trimester
More invasive 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%. After 10 weeks
More invasive 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). By amniocentesis is also possible to cryopreserve amniotic stem cells. After 15 weeks
More invasive Embryoscopy 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.
More invasive Percutaneous umbilical cord blood sampling
Advances in Prenatal Screening
Measurement of fetal proteins in maternal serum is a part of standard prenatal screening for fetal aneuploidy and neural tube defects. Computational predictive model shows that extensive and diverse feto-maternal protein trafficking occurs during pregnancy and can be readily detected non-invasively in maternal whole blood. This computational approach circumvented a major limitation, the abundance of maternal proteins interfering with the detection of fetal proteins, to fetal proteomic analysis of maternal blood. Entering fetal gene transcripts previously identified in maternal whole blood into a computational predictive model helped develop a comprehensive proteomic network of the term neonate. It also shows that the fetal proteins detected in pregnant woman’s blood originate from a diverse group of tissues and organs from the developing fetus. Development proteomic networks dominate the functional characterization of the predicted proteins, illustrating the potential clinical application of this technology as a way to monitor normal and abnormal fetal development.
The difference in methylation of specific DNA sequences between mother and fetus can be used to identify fetal-specific DNA in the blood circulation of the mother. In a study published in 6 March 2011 online issue of Nature journal, using this non-invasive technique a group of investigators from Greece and UK achieved correct diagnosis of 14 trisomy 21 (Down Syndrome) and 26 normal cases.
Typical screening sequence
California provides a useful guide to most of the currently available screening paradigms.
At early presentation of pregnancy at around 6 weeks, 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%.
Alternatively, 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). With integrated screening, both a First Trimester Combined Test and a Triple/Quad test is performed, and a report is only produced after both tests have been analyzed. However patients may not wish to wait between these two sets of test. 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 (risk score between 1:50 and 1:2000) 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. The First Trimester Combined Test and the Triple/Quad test together have a sensitivity of 88-95% with a 5% false-positive rate for Down Syndrome, though they can also be analyzed in such a way as to offer a 90% sensitivity with a 2% false-positive rate.
Conditions typically tested for
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 abnormalities.
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, intrauterine 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.
Ethical and practical issues
Ethical issues of prenatal testing
The option to continue or abort 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 (for example, sex selection).
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.
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. However in the US, there are prenatal surgeries for spina bifida fetus. Early diagnosis gives the parents time to research and discuss post-natal treatment and care, or in some cases, abortion. Genetic counselors are usually called upon to help families make informed decisions regarding results of prenatal diagnosis.
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[citation needed]. 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. The quad test would also tell 5% (~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% of the high risk pool) 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 a miscarriage 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" needlessly worry until they get the results back from their invasive procedure and find out that their pregnancy is normal.
By comparison, in the same 4000 women, a screening test that has a 99% sensitivity and a 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, often 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).
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. Most obstetricians (depending on the country) 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.
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.
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