Prenatal testing is
testingIn scientific research, an experiment is a method of investigating causal relationships among variables, or to test a hypothesis. An experiment is a cornerstone of the empirical approach to acquiring data about the world and is used in both natural sciences and social sciences...
for diseases or conditions in a
fetusA fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth. The plural is fetuses....
or
embryoAn embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
before it is born. The aim is to detect birth defects such as neural tube defects,
Down syndromeDown syndrome , Down's syndrome , trisomy 21, or trisomy G is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British doctor who described the syndrome in 1866...
,
chromosomeA chromosome is an organized structure of DNA and protein that is found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions...
abnormalities, genetic diseases and other conditions, such as
spina bifidaSpina bifida is a developmental birth defect caused by the incomplete closure of the embryonic neural tube. Some vertebrae overlying the spinal cord are not fully formed and remain unfused and open. If the opening is large enough, this allows a portion of the spinal cord to stick out through the...
, cleft palate, Tay Sachs disease, sickle cell anemia,
thalassemiaThalassemia is an inherited autosomal co-dominant blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin...
,
cystic fibrosisCystic fibrosis is a genetic disorder known to be an inherited disease of the secretory glands, including the glands that make mucus and sweat....
, and
fragile x syndromeFragile X syndrome, or Martin-Bell syndrome, is a genetic syndrome which results in a spectrum of characteristic physical, intellectual, emotional and behavioural features which range from severe to mild in manifestation....
. Screening can also determine the
sexIn biology, sex is a process of combining and mixing genetic traits, often resulting in the specialization of organisms into a male or female variety . Sexual reproduction involves combining specialized cells to form offspring that inherit traits from both parents...
of the fetus. Common testing procedures include
amniocentesisAmniocentesis , is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections , in which a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined...
,
sonogramA sonogram may refer to the following:* A diagnostic medical image created using ultrasound echo equipment, see Medical ultrasonography....
s, nuchal translucency ultrasound, serum marker testing, or genetic screening. In some cases, the tests are administered to determine if the fetus will be
abortedAn abortion is the termination of a pregnancy by the removal or expulsion from the uterus of a fetus or embryo. An abortion can occur spontaneously due to complications during pregnancy or can be induced, in humans and other species...
, 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.
amniocentesisAmniocentesis , is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections , in which a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined...
, which can be done from about 14 weeks gestation, and usually up to about 20 weeks, and
chorionic villus samplingChorionic villus sampling is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails getting a sample of the chorionic villus and testing it...
, 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-fetoproteinAlpha-fetoprotein is a protein that in humans is encoded by the AFP gene.This gene encodes alpha-fetoprotein, a major plasma protein produced by the yolk sac and the liver during fetal life. The protein is thought to be the fetal counterpart of serum albumin, and the alpha-fetoprotein and albumin...
). Non-invasive genetic 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 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
femaleFemale is the sex of an organism, or a part of an organism, which produces mobile ova .- Defining Characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
, it is sometimes aborted. The rise of designer babies and parental selection for specific traits raises a host of
bioethicalBioethics is the philosophical study of the ethical controversies brought about by advances in biology and medicine. Bioethicists are concerned with the ethical questions that arise in the relationships among life sciences, biotechnology, medicine, politics, law, philosophy, and theology.- History...
and legal issues that will dominate
reproductive rightsReproductive rights are a series of legal rights and freedoms relating to reproduction and reproductive health. The World Health Organisation defines reproductive rights as follows:...
debates in the 21st century.
Fetal versus maternal
Some screening tests performed on the woman are intended to detect traits or characteristics of the
fetusA fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth. The plural is fetuses....
. Others detect conditions in the woman that may have an
adverse effectIn medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect, and may result from an unsuitable or incorrect dosage or...
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-eclampsiaPre-eclampsia is a medical condition where hypertension arises in pregnancy in association with significant amounts of protein in the urine. Because pre-eclampsia refers to a set of symptoms rather than any causative factor, it is established that there are many different causes for the syndrome...
, 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" 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
amniocentesisAmniocentesis , is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections , in which a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined...
with
karyotypingA karyotype is the charcteristic chromosome complement of a eukaryote species. The term may also be used of a cell, or an individual. The preparation and study of karyotypes is part of cytogenetics....
, and prenatal
ultrasoundUltrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Although this limit varies from person to person, it is approximately 20 kilohertz in healthy, young adults and thus, 20 kHz serves as a useful lower limit in describing 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.
Non-invasive methods
- Examination of the woman's uterus
The uterus is a major female hormone-responsive reproductive sex organ of most mammals, including humans. It is within the uterus that the fetus develops during gestation. The term uterus is used consistently within the medical and related professions; the Germanic term, womb is more common in...
from outside the body.
- Ultrasound detection
Obstetric sonography is the application of medical ultrasonography to obstetrics, in which sonography is used to visualize the embryo or fetus in its mother's uterus...
- Commonly dating scans (sometimes known as booking scans) from 7 weeks to confirm pregnancy dates and look for twinTwins are two offspring resulting from the same pregnancy, usually born in close succession. They can be the same or different sex. Twins can either be monozygotic or dizygotic ....
s. The specialised nuchal scanA nuchal scan is a sonographic prenatal screening scan to help identify higher risks of Down syndrome in a fetus, particularly for older women who have higher risks of such pregnancies. The scan is carried out at 11–13 weeks pregnancy and assesses the amount of fluid behind the neck of the fetus -...
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
The stethoscope is an acoustic medical device for auscultation, or listening to the internal sounds of an animal body. It is often used to listen to heart sounds. It is also used to listen to intestines and blood flow in arteries and veins...
)
- External fetal monitoring, often known as a non-stress test
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
Human chorionic gonadotropin or Human chorionic gonadotrophin is a glycoprotein hormone produced in pregnancy that is made by the developing embryo soon after conception and later by the syncytiotrophoblast...
, inhibin-A, estriolEstriol is one of the three main estrogens produced by the human body.-Synthesis and levels:It is only produced in significant amounts during pregnancy as it is made by the placenta from 16-OHDHEAS, an androgen steroid made in the fetal liver and adrenal glands.The Human placenta produces...
, and h-hCG (hyperglycosolated hCG) in the woman's serumBlood plasma is the yellow liquid component of blood, in which the blood cells in whole blood would normally be suspended. It makes up about 55% of the total blood volume. It is mostly water and contains dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon dioxide...
.
- First trimester maternal serum screening can check levels of free β-hCG
Human chorionic gonadotropin or Human chorionic gonadotrophin is a glycoprotein hormone produced in pregnancy that is made by the developing embryo soon after conception and later by the syncytiotrophoblast...
, PAPP-APregnancy-associated plasma protein A, pappalysin 1, also known as PAPPA, is a protein used in screening tests for Down syndrome.This gene encodes a secreted metalloproteinase which cleaves insulin-like growth factor binding proteins . It is thought to be involved in local proliferative processes...
, intact or beta hCG, inhibin-A, or h-hCG in the woman's serumBlood plasma is the yellow liquid component of blood, in which the blood cells in whole blood would normally be suspended. It makes up about 55% of the total blood volume. It is mostly water and contains dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon dioxide...
, 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
Baby Gender Mentor is the trade name of a controversial blood test designed to determine whether a pregnant woman is carrying a male or female child. The test is made by Acu-Gen Biolab, Inc., a biotech company in Lowell, Massachusetts, United States, and is marketed to detect the sex of a fetus as...
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 aneuploidyFetal aneuploidy is not as common as other birth defects, affecting 9 in 1000 births and increasing with maternal age. Amniocentesis and chorionic villus sampling have historically been two of the most popular methods used to detect fetal aneuploidy. Since these procedures are invasive, they may...
. 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.
- Preimplantation Genetic Diagnosis
In medicine and genetics preimplantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
(PGD) - During in vitro fertilization (IVF) procedures, it is possible to sample cells from human embryos prior the implantation.
More invasive methods
- Chorionic villus sampling
Chorionic villus sampling is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails getting a sample of the chorionic villus and testing it...
- 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
Amniocentesis , is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections , in which a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined...
- This can be done once enough amniotic fluidAmniotic fluid or liquor amnii is the nourishing and protecting liquid contained by the amniotic sac of a pregnant woman. The amniotic sac grows and begins to fill, mainly with water, around two weeks after fertilization. After a further 10 weeks the liquid contains proteins, carbohydrates, lipids...
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
Fetoscopy is an endoscopic procedure during pregnancy to allow access to the fetus, the amniotic cavity, the umbilical cord, and the fetal side of the placenta. A small incision is made in the abdomen, and an endoscope is inserted through the abdominal wall and uterus into the amniotic cavity...
- 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.
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.
ACOGThe American College of Obstetricians and Gynecologists is a professional association of medical doctors specializing in obstetrics and gynecology in the United States. It has a membership of over 52,000 and represents 90 percent of U.S...
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
Lupus erythematosus is a connective tissue disease. Lupus is a chronic inflammatory disease that occurs when the body's immune system attacks its own tissues and organs. Inflammation caused by lupus can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
, diabetes, asthmaAsthma is a predisposition to chronic inflammation of the lungs in which the airways are reversibly narrowed. Asthma affects 7% of the population of the United States, and 300 million worldwide...
, or epilepsyEpilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures...
- 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
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, and early dating ultrasound scan may be offered to help confirm the
gestational ageGestational age is the age of an embryo or fetus . In humans, a common method of calculating gestational age starts counting either from the first day of the woman's last menstrual period or from 14 days before conception . Counting from the first day of the LMP involves the assumption that...
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 scanA nuchal scan is a sonographic prenatal screening scan to help identify higher risks of Down syndrome in a fetus, particularly for older women who have higher risks of such pregnancies. The scan is carried out at 11–13 weeks pregnancy and assesses the amount of fluid behind the neck of the fetus -...
(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 samplingChorionic villus sampling is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails getting a sample of the chorionic villus and testing it...
(CVS) available from 9 weeks, or the second trimester
amniocentesisAmniocentesis , is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections , in which a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined...
, 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.
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.
Ethical issues of prenatal testing
- The option to continue or abort a pregnancy is the primary choice after most prenatal testing. Rarely, fetal intervention
Fetal intervention involves in utero surgical treatment of a fetus. Procedures include open fetal surgery, the most invasive, and the less invasive fetendo and fetal image-guided surgery.Fetal intervention is relatively new...
corrective procedures are possible.
- Are the risks of prenatal diagnosis, such as amniocentesis
Amniocentesis , is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections , in which a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined...
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
Spina bifida is a developmental birth defect caused by the incomplete closure of the embryonic neural tube. Some vertebrae overlying the spinal cord are not fully formed and remain unfused and open. If the opening is large enough, this allows a portion of the spinal cord to stick out through the...
and teratomaA teratoma is a kind of tumor . Definitive diagnosis of a teratoma is based on its histology. A teratoma is a tumor with tissue or organ components resembling normal derivatives of all three germ layers. There are rare occasions when not all three germ layers are identifiable...
before birth may give the option of fetal surgeryFetal surgery covers a broad range of surgical techniques used in treatment of birth defects where the fetus is operated on while still in the pregnant uterus. Open fetal surgery involves completely opening up the uterus in order to operate on the fetus...
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
The term wrongful abortion refers to an abortion that a pregnant woman undergoes as a result of negligent or malicious conduct by a physician or health care provider.-Misinformation about pregnancy:...
.
Will the result of the test affect treatment of the fetus?
In some genetic conditions, for instance
cystic fibrosisCystic fibrosis is a genetic disorder known to be an inherited disease of the secretory glands, including the glands that make mucus and sweat....
, 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
abortionAn abortion is the termination of a pregnancy by the removal or expulsion from the uterus of a fetus or embryo. An abortion can occur spontaneously due to complications during pregnancy or can be induced, in humans and other species...
.
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 counselingGenetic counseling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent, avoid...
can 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 bifidaSpina bifida is a developmental birth defect caused by the incomplete closure of the embryonic neural tube. Some vertebrae overlying the spinal cord are not fully formed and remain unfused and open. If the opening is large enough, this allows a portion of the spinal cord to stick out through the...
. Ultrasound results may also show "soft signs," such as an
Echogenic intracardiac focusEchogenic intracardiac focus is a small bright spot seen in the baby’s heart on an ultrasound exam. This is thought to represent mineralization, or small deposits of calcium, in the muscle of the heart. EIFs are found in about 3-5% of normal pregnancies and cause no health problems.EIFs...
or a
Choroid plexus cystChoroid plexus cysts are cysts that occur within choroid plexus of the brain. The brain contains pockets or spaces called ventricles with a spongy layer of cells and blood vessels called the choroid plexus. This is in the middle of the fetal brain. The choroid plexus has the important function...
, which are usually normal, but can be associated with an increased risk for
chromosomeA chromosome is an organized structure of DNA and protein that is found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions...
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 positiveIn statistics, the terms type I error and type II error are used to describe possible errors made in a statistical decision process...
s and
false negativeIn statistics, the terms type I error and type II error are used to describe possible errors made in a statistical decision process...
s will have a large impact on a couple when they are told the result, or when the child is born.
DiagnosticIn medicine, diagnosis is a label given for a medical condition or disease identified by its signs, symptoms, and from the results of various diagnostic procedures...
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 AFPAlpha-fetoprotein is a protein that in humans is encoded by the AFP gene.This gene encodes alpha-fetoprotein, a major plasma protein produced by the yolk sac and the liver during fetal life. The protein is thought to be the fetal counterpart of serum albumin, and the alpha-fetoprotein and albumin...
level indicates a greater risk for anencephaly and open spina bifida. This screening is 80% and 90% sensitive for spina bifida and anencephaly, respectively.
Amniotic fluid
acetylcholinesteraseAcetylcholinesterase, also known as AChE, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic synapses in the central nervous system, where its activity serves to terminate synaptic...
and
AFPAlpha-fetoprotein is a protein that in humans is encoded by the AFP gene.This gene encodes alpha-fetoprotein, a major plasma protein produced by the yolk sac and the liver during fetal life. The protein is thought to be the fetal counterpart of serum albumin, and the alpha-fetoprotein and albumin...
level are more sensitive and
specificSpecific can mean:* ParticularIn science, specific can denote that a measurement is expressed per unit mass :* Specific heat capacity* Specific energy* Specific impulseor is relative to a standard value:...
than AFP in predicting neural tube defects.
Many maternal-fetal specialists do not bother 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.
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 testThe triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy in the second trimester. The Triple test measures serum levels of AFP, estriol, and beta-hCG, with a 70% sensitivity and 5% false-positive rate...
,
HIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid,...
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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