Prenatal diagnosis
Encyclopedia
Prenatal diagnosis or prenatal screening 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 be used for prenatal sex discernment
. Common testing procedures include amniocentesis
, ultrasonography
including 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.
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.
, 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
). Blood tests for select trisomies (Down syndrome in the United States, Down and Edwards syndromes in China) based on detecting fetal DNA present in maternal blood have become available.. 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.
. 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.
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.
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.
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.
s 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 March 6, 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. Using massive parallel sequencing
, a study testing for trisomy 21 only, successfully detected 209 of 212 cases (98.6%) with 3 false-positives in 1,471 pregnancies (0.2%). With commercially available non-invasive (blood) testing for Down syndrome having become available to patients in the United States and already available in China, in October 2012, the International Society for Prenatal Diagnosis created some guidance. Based on its sensitivity and specificity
, it constitutes an advanced screening test and that positive results require confirmation by an invasive test, and that while effective in the diagnosis of Down syndrome, it cannot assess half the abnormalities detected by invasive testing. The test is not recommended for general use until results from broader studies have been reported, but may be useful in high-risk patients in conjunction with genetic counseling.
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.
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.
(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.
, 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.
. 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 positive
s and false negative
s 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.
Amniotic fluid acetylcholinesterase
and AFP
level are more sensitive and specific
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.
, 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.
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.
Experiment
An experiment is a methodical procedure carried out with the goal of verifying, falsifying, or establishing the validity of a hypothesis. Experiments vary greatly in their goal and scale, but always rely on repeatable procedure and logical analysis of the results...
for diseases or conditions in a fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
or embryo
Embryo
An 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 syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
, chromosome
Chromosome
A chromosome is an organized structure of DNA and protein 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.Chromosomes...
abnormalities, genetic diseases and other conditions, such as spina bifida
Spina bifida
Spina bifida is a developmental congenital disorder caused by the incomplete closing 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 protrude through...
, cleft palate, Tay Sachs disease, sickle cell anemia, thalassemia
Thalassemia
Thalassemia is an inherited autosomal recessive blood disease that originated in the Mediterranean region. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin...
, cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
, and fragile x syndrome
Fragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
. Screening can also be used for prenatal sex discernment
Prenatal sex discernment
Prenatal sex discernment is the prenatal testing for discerning the sex of a fetus before birth.-Methods:Prenatal sex discernment can be performed by preimplantation genetic diagnosis before conception....
. Common testing procedures include amniocentesis
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 sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
, ultrasonography
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
including nuchal translucency ultrasound, serum marker testing, or genetic screening. In some cases, the tests are administered to determine if the fetus will be aborted
Abortion
Abortion is defined as the termination of pregnancy by the removal or expulsion from the uterus of a fetus or embryo prior to viability. An abortion can occur spontaneously, in which case it is usually called a miscarriage, or it can be purposely induced...
, 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.
Fetal screening has also been done to determine characteristics generally not considered birth defects, and avail for e.g. sex selection
Sex selection
Sex selection is the attempt to control the sex of the offspring to achieve a desired sex. It can be accomplished in several ways, both pre- and post-implantation of an embryo, as well as at birth...
. The rise of designer babies and parental selection for specific traits raises a host of bioethical
Bioethics
Bioethics is the study of controversial ethics 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, and philosophy....
and legal issues that will dominate reproductive rights
Reproductive rights
Reproductive rights are legal rights and freedoms relating to reproduction and reproductive health. The World Health Organization defines reproductive rights as follows:...
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 uterusUterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, e.g. amniocentesis
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 sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
, which can be done from about 14 weeks gestation, and usually up to about 20 weeks, and chorionic villus sampling
Chorionic villus sampling
Chorionic villus sampling , sometimes misspelled "chorionic villous sampling", is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it...
, 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
Alpha-fetoprotein
Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene....
). Blood tests for select trisomies (Down syndrome in the United States, Down and Edwards syndromes in China) based on detecting fetal DNA present in maternal blood have become available.. 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 fetusFetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
. Others detect conditions in the woman that may have an adverse effect
Adverse effect
In 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. If it results 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
Pregnancy-associated plasma protein A
Pregnancy-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...
have been shown to correspond to an increased risk of pre-eclampsia
Pre-eclampsia
Pre-eclampsia or preeclampsia is a medical condition in which hypertension arises in pregnancy in association with significant amounts of protein in the urine....
, 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.
Many expectant parents would like to know the sex of their baby before birth. Methods include amniocentesis
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 sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
with karyotyping
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
, and prenatal ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
. 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.
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, lupusLupus erythematosusLupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
, diabetes, asthmaAsthmaAsthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, or epilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases... - 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 |
| 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. | First trimester |
| Cell-free Fetal DNA in Maternal Blood | Based on DNA of fetal origin circulating in the maternal blood. Testing can potentially identify fetal aneuploidy Diagnosis of fetal aneuploidy Fetal 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... (available in the United States, beginning 2011) and gender Baby Gender Mentor Baby Gender Mentor is the trade name of a controversial blood test designed for prenatal sex discernment, that is, 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... of a fetus as early as six weeks into a pregnancy. Fetal DNA ranges from about 2-10% of the total DNA in maternal blood. |
First trimester |
| Preimplantation Genetic Diagnosis Preimplantation genetic diagnosis In medicine and genetics pre-implantation 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. PGD is in itself non-invasive, but IVF usually involves invasive procedures such as transvaginal oocyte retrieval Transvaginal oocyte retrieval Transvaginal oocyte retrieval , also referred to as oocyte retrieval or even simply egg collection, is a technique used in in vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body... |
>- | External examination | Examination of the woman's uterus Uterus The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species... from outside the body. |
>- | Ultrasound detection Obstetric ultrasonography Obstetric sonography is the application of medical ultrasonography to obstetrics, in which sonography is used to visualize the embryo or foetus in its mother's uterus... |
Commonly dating scans (sometimes known as booking scans) from 7 weeks to confirm pregnancy dates and look for twin Twin A twin is one of two offspring produced in the same pregnancy. Twins can either be monozygotic , meaning that they develop from one zygote that splits and forms two embryos, or dizygotic because they develop from two separate eggs that are fertilized by two separate sperm.In contrast, a fetus... s. The specialised nuchal scan Nuchal scan A nuchal scan is a sonographic prenatal screening scan to help identify higher risks of chromosomal defects including Down's syndrome in a fetus, particularly for older women who have higher risks of such pregnancies. High thickness measurements are also associated with congenital heart defect... 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. |
>- | Fetal heartbeat | Listening to the fetal heartbeat (see stethoscope 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 lung and heart sounds. It is also used to listen to intestines and blood flow in arteries and veins... ) |
>- | Non-stress test | Use of cardiotocography Cardiotocography In medicine , cardiotocography is a technical means of recording the fetal heartbeat and the uterine contractions during pregnancy, typically in the third trimester... during the third trimester to monitor fetal wellbeing |
>- | Maternal serum screening (triple test Triple test The triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy in the second trimester to classify a patient as either high-risk or low-risk for chromosomal abnormalities .The term "multiple-marker screening test" is sometimes used... ) |
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 Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not... , inhibin-A, estriol Estriol Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human... , and h-hCG (hyperglycosolated hCG) in the woman's serum Blood plasma Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid... . |
>- | Transcervical Transcervical Transcervical refers to a transluminal procedure through the cervix of the uterus, including:*Transcervical sterilization*Transcervical chorionic villus sampling... 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 Ectopic pregnancy An ectopic pregnancy, or eccysis , is a complication of pregnancy in which the embryo implants outside the uterine cavity. With rare exceptions, ectopic pregnancies are not viable. Furthermore, they are dangerous for the parent, since internal haemorrhage is a life threatening complication... or anembryonic gestation Anembryonic gestation An anembryonic gestation is a pregnancy in which the very early pregnancy appears normal on an ultrasound scan, but as the pregnancy progresses a visible embryo never develops... . |
>- | Maternal serum screening (triple test Triple test The triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy in the second trimester to classify a patient as either high-risk or low-risk for chromosomal abnormalities .The term "multiple-marker screening test" is sometimes used... ) |
First trimester maternal serum screening can check levels of free β-hCG Human chorionic gonadotropin Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not... , PAPP-A Pregnancy-associated plasma protein A Pregnancy-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 serum Blood plasma Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid... , and combine these with the measurement of nuchal translucency (NT). Some institutions also look for the presence of a fetal nasalbone on the ultrasound. |
>- | Chorionic villus sampling Chorionic villus sampling Chorionic villus sampling , sometimes misspelled "chorionic villous sampling", is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling 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 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 sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for... |
This can be done once enough amniotic fluid Amniotic fluid Amniotic fluid or liquor amnii is the nourishing and protecting liquid contained by the amniotic sac of a pregnant woman.- Development of 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 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 sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for... is also possible to cryopreserve amniotic stem cells Amniotic stem cells Amniotic stem cells are multipotent stem cells of mesenchymal origin extracted from amniotic fluid.Amniotic stem cells are able to differentiate into various tissue type such as skin, cartilage, cardiac tissue, nerves, muscle, and bone, and may have potential future medical applications.All over... . |
>- | Embryoscopy and fetoscopy 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. |
| Percutaneous umbilical cord blood sampling Percutaneous umbilical cord blood sampling Percutaneous umbilical cord blood sampling , also called cordocentesis, is a diagnostic genetic test that examines blood from the fetal umbilical cord to detect fetal abnormalities. PUBS provides a means of rapid chromosome analysis and is useful when information cannot be obtained through... |
Advances in Prenatal Screening
Measurement of fetal proteinFetal protein
Fetal proteins are simply proteins present at highest levels at the fetus stage. Often related proteins assume similar roles after birth or in the embryo, in which case the fetal varieties are called fetal isoforms...
s in maternal serum is a part of standard prenatal screening for fetal aneuploidy
Diagnosis of fetal aneuploidy
Fetal 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...
and neural tube defects
Neural tube defects
Neural tube defects are one of the most common birth defects, occurring in approximately one in 1,000 live births in the United States. An NTD is an opening in the spinal cord or brain that occurs very early in human development. In the 2nd week of pregnancy called gastrulation, specialized cells...
. 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
Whole blood
Whole blood is a term used in transfusion medicine for human blood from a standard blood donation. The blood is typically combined with an anticoagulant during the collection process, but is generally otherwise unprocessed...
. 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
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
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 March 6, 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
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
) and 26 normal cases. Using massive parallel sequencing
Massive parallel sequencing
Massive Parallel Sequencing is a term used to describe several revolutionary approaches to DNA sequencing, the so-called next-generation sequencing technologies or second generation sequencing. These sequencing technologies have emerged in late 1996 an have become commercially available since 2005...
, a study testing for trisomy 21 only, successfully detected 209 of 212 cases (98.6%) with 3 false-positives in 1,471 pregnancies (0.2%). With commercially available non-invasive (blood) testing for Down syndrome having become available to patients in the United States and already available in China, in October 2012, the International Society for Prenatal Diagnosis created some guidance. Based on its sensitivity and specificity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
, it constitutes an advanced screening test and that positive results require confirmation by an invasive test, and that while effective in the diagnosis of Down syndrome, it cannot assess half the abnormalities detected by invasive testing. The test is not recommended for general use until results from broader studies have been reported, but may be useful in high-risk patients in conjunction with genetic counseling.
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
Gestational age
Gestational age relates to the age of an embryo or fetus . There is some ambiguity in how it is defined:*In embryology, gestational age is the time elapsed since conception. This interval is also termed fertilisation 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
Nuchal scan
A nuchal scan is a sonographic prenatal screening scan to help identify higher risks of chromosomal defects including Down's syndrome in a fetus, particularly for older women who have higher risks of such pregnancies. High thickness measurements are also associated with congenital heart defect...
(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.
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.
Conditions typically tested for
Use of NT ultrasound will screen for Down SyndromeDown syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
(Trisomy 21), Edwards Syndrome (Trisomy 18), and Patau Syndrome
Patau syndrome
Patau syndrome, also known as trisomy 13 and trisomy D, is a chromosomal abnormality, a syndrome in which a patient has an additional chromosome 13 due to a nondisjunction of chromosomes during meiosis. Some are caused by Robertsonian translocations...
(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 SyndromeSmith-Lemli-Opitz syndromeSmith-Lemli-Opitz syndrome is an autosomal recessive metabolic and developmental congenital disorder that causes the inability to correctly produce or synthesize cholesterol due to a low occurrence of the 7-DHC reductace enzyme.-Symptoms:The signs and symptoms of SLOS syndrome vary widely...
(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 issues of prenatal testing
- The option to continue or abort a pregnancy is the primary choice after most prenatal testing. Rarely, fetal interventionFetal interventionFetal 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 amniocentesisAmniocentesisAmniocentesis 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 sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
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 bifidaSpina bifidaSpina bifida is a developmental congenital disorder caused by the incomplete closing 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 protrude through...
and teratomaTeratomaA teratoma is an encapsulated 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 surgeryFetal surgery is any of a broad range of surgical techniques that are used to treat birth defects in fetuses who are still in the pregnant uterus.* Open fetal surgery involves completely opening the uterus 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 abortionWrongful abortionThe 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
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
, 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
Spina bifida
Spina bifida is a developmental congenital disorder caused by the incomplete closing 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 protrude through...
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 bifidaSpina bifida
Spina bifida is a developmental congenital disorder caused by the incomplete closing 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 protrude through...
. Ultrasound results may also show "soft signs," such as an Echogenic intracardiac focus
Echogenic intracardiac focus
Echogenic 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 cyst
Choroid plexus cyst
Choroid 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 chromosome
Chromosome
A chromosome is an organized structure of DNA and protein 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.Chromosomes...
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 positive
Type I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...
s and false negative
Type I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...
s will have a large impact on a couple when they are told the result, or when the child is born. Diagnostic
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
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
Alpha-fetoprotein
Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene....
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 acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
and AFP
Alpha-fetoprotein
Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene....
level are more sensitive and specific
Specific
Specific may refer to:* Specificity* Specific, a cure or therapy for a specific illnessLaw:* Specific deterrence, focussed on an individual* Specific finding, intermediate verdict used by a jury in determining the final verdict...
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. Most obstetricians (depending on the country) offer patients the AFP triple testTriple test
The triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy in the second trimester to classify a patient as either high-risk or low-risk for chromosomal abnormalities .The term "multiple-marker screening test" is sometimes used...
, HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
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.
See also
- Genetic counselingGenetic counselingGenetic counseling or traveling 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...
- AmniocentesisAmniocentesisAmniocentesis 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 sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
- Amniotic stem cell
- Amniotic stem cell bankAmniotic stem cell bankAn amniotic stem cell bank is a facility that stores stem cells derived from amniotic fluid for future use. Stem cell samples in private banks are stored specifically for the use by the individual person from who such cells have been collected and the banking costs are paid by such person...
- Chorionic villiChorionic villiChorionic villi are villi that sprout from the chorion in order to give a maximum area of contact with the maternal blood.Embryonic blood is carried to the villi by the branches of the umbilical arteries, and after circulating through the capillaries of the villi, is returned to the embryo by the...