Prenatal diagnosis


See noninvasive prenatal testing

Prenatal diagnosis or prenatal screening refers to testing for diseases or conditions in a fetus or embryo before it is born.

Prenatal testing is an established part of obstetric care.

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.

The aim is to detect birth defects such as neural tube defects, Down syndrome, chromosome abnormalities, genetic disorders and other conditions, such as spina bifida, cleft palate, Tay Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, Muscular dystrophy, and fragile X syndrome.

Quantitative differences in chromosome fragments in maternal blood can be used to distinguish fetuses affected with trisomy 21, and a few other fetal aneuploidies, from those that are not affected.

Testing can be done any time after 10 weeks and is typically done between 10-22 weeks.

Screening can also be used to determined prenatal sex.

Common prenatal testing procedures include amniocentesis, ultrasonography including nuchal translucency ultrasound, serum marker testing, or genetic screening.

The tests are administered to determine if the fetus will be aborted.

Prenatal testing is useful to diagnose high-risk pregnancy so delivery can be scheduled in a tertiary care hospital where the baby can receive appropriate care.

Maternal indications for NIPT are:

singleton pregnancies at high risk for trisomy 21 due to:

advanced maternal age

an abnormal serum screen

personal or family history of aneuploidy

abnormal ultrasound

Some analyses include twin pregnancies, and Turner syndrome

Prenatal testing can be invasive or non-invasive in nature.

Invasive methods involve probes or needles inserted into the uterus, e.g. amniocentesis, and chorionic villus sampling.

Amniocentesis can be done from about 14 weeks gestation, and up to about 20 weeks..

Chorionic villus sampling can be done earlier, between 9.5 and 12.5 weeks gestation.

Chorionic villus sampling may be slightly more risky to the fetus.

Comparing transabdominal chorionic villus sampling with second trimester amniocentesis indicates no significant difference in the total pregnancy loss between the two procedures.

Non-invasive techniques include examinations through ultrasonography and maternal serum screens.

Blood tests for select trisomies like Down syndrome 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.

Some screening tests performed on the woman can detect traits or characteristics of the fetus.

Some screening tests can detect conditions in the woman that may have an adverse effect on the fetus, or that threaten the pregnancy.

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.

Miscarriage and fetal damage risks associated with amniocentesis and chorionic villus 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.

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, and a risk score of 1:300 would therefore be considered low-risk by many physicians.

It is recommended that all pregnant women, regardless of age, be offered invasive testing to obtain a definitive diagnosis of certain birth defects.

The risk of birth defects is high enough to warrant skipping screening and going straight for invasive testing for the following:

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 hypertension,lupus, diabetes, asthma, or epilepsy

Women who have family histories or ethnic backgrounds prone to genetic disorders.

Women who are pregnant with multiple geststations

Women who have previously had miscarriages

Methods of prenatal screening and diagnosis

Fetal cells which circulate in maternal blood and hold all the genetic information of the developing fetus, they can be used to perform prenatal diagnosis.

Based on DNA of fetal origin circulating in the maternal blood testing can potentially identify fetal aneuploidy and gender 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.

Cell-free fetal DNA also allows whole genome sequencing of the fetus, thus determining the complete DNA sequence of every gene.

Clinical diagnosis has historically been performed with G-banded karyotyping to detect chromosomal abnormalities.
G-banded karyotyping results in the diagnosis in 9-19% of fetal anomalies, and chromosomal MicroArray analysis provides an additional 6% yield: the cause of the majority of fetal anomalies remains unknown.

Exome sequencing shows diagnostic yield of 8.5-10% of fetal anomalies.

During in vitro fertilization procedures, it is possible to sample cells from human embryos before implantation.

Non-invasive ultrasound detection from 7 weeks to confirm pregnancy dates and look for twins.

The specialised nuchal ultrasound scan at 11–13 weeks may be used to identify higher risks of Downs syndrome.

Ultrasound scans from 18 weeks may check for any abnormal development.

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%.

Fetal cells can be used for fetal sex determination and identify aneuploidies.

Recoverable trophoblast cells diminish in abnormal gestations, such as in ectopic pregnancy or anembryonic gestation.

First trimester less invasive analysis includes maternal serum screening including β-hCG, PAPP-A, alpha fetoprotein, inhibin-A.

First or second trimester studies include more invasive chorionic villus sampling.

Chorionic villus sampling involves getting a sample of the chorionic villus and testing it.

Chorionic villus sampling can be done earlier than amniocentesis, but may have a higher risk of miscarriage, estimated at 1%.

After 10 weeks the more invasive amniocentesis can be done once enough amniotic fluid has developed to be sampled.

Cells from the fetus will be floating in amniotic fluid can be separated and tested.

Miscarriage risk of amniocentesis is commonly quoted as 0.06% (1:1600).

It is also possible to cryopreserve amniotic stem cells.

After 15 weeks more invasive embryoscopy and fetoscopy can be done, by putting a probe into a women’s uterus to observe, or to sample blood or tissue from the embryo or fetus.

Percutaneous umbilical cord blood sampling is a diagnostic genetic test that examines blood from the fetal umbilical cord to detect fetal abnormalities at 24–34 weeks.

First trimester maternal serum screening can check levels of free β-hCG, PAPP-A, intact or beta hCG, or h-hCG in the woman’s serum, and combine these with the measurement of nuchal translucency (NT).

Second trimester maternal serum screening can check levels of alpha fetoprotein, β-hCG, inhibin-A, estriol, and h-hCG (hyperglycosolated hCG) in the woman’s serum.

The triple test measures serum levels of AFP, estriol, and beta-hCG, with a 70% sensitivity and 5% false-positive rate for Down syndrome.

The Quad test which adds inhibin A to the panel, resulting in an 81% sensitivity and 5% false-positive rate for detecting Down syndrome when taken at 15–18 weeks of gestational age.

The biomarkers PAPP-A and β-hCG seem to be altered for pregnancies resulting from ICSI, causing a higher false-positive rate.

Correction factors should be used when screening for Down’s syndrome in singleton pregnancies after ICSI, but in twin pregnancies such correction factors have not been fully elucidated.

In vanishing twin pregnancies with a second gestational sac with a dead fetus, first trimester screening should be based solely on the maternal age and the nuchal translucency scan as biomarkers are altered in these cases.

Measurement of fetal proteins in maternal serum is a part of standard prenatal screening for fetal aneuploidy and neural tube defects.

Feto-maternal protein trafficking occurs during pregnancy and can be readily detected non-invasively in maternal whole blood.

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.

Around weeks 10–11, nuchal thickness scan (NT) 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 blood tests are then 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 to detect rate for abnormalities of 82–87% and a false-positive rate around 5%.

Patients with moderate risk scores between 1:50 and 1:2000 Qsubmit a second trimester sample.

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.

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.

A 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.

Ultrasound for nuchal translucency can screen for aneuploidy such as Down Syndrome (Trisomy 21), Edwards Syndrome (Trisomy 18), and Patau Syndrome (Trisomy 13).

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, 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 regardless of her AFP level, which makes the AFP score unnecessary.

Interphase-fluorescence in situ hybridization (FISH), quantitative PCR and direct preparation of chromosomes from chorionic villi are methods being used that are the most effective for detecting fetal aneuploidy.

Noninvasive diagnosis of fetal aneuploidy is becoming more common

due to the detection of fetal cells and fetal DNA circulating in maternal blood.

The key problem is that circulating fetal nucleated cells comprise only three to six percent of maternal blood plasma DNA.

There are 2 effective approaches used for the detection of fetal aneuploidy.

The first involves the measuring of the allelic ratio of single nucleotide polymorphisms (SNPs) in the mRNA coding region in the placenta.

The second is analyzing both maternal and fetal DNA and looking for differences in the DNA methylation patterns.

Fetal cell DNA in maternal blood plasma is elevated in pregnancies complicated by fetal trisomy 21, 13 and 18, making it easier to acquire enough sample sizes of maternal blood plasma to test for fetal aneuploidy.

Digital PCR can be used to differentiate between normal and aneuploid DNA using fetal DNA in the maternal blood plasma.

Very low estriol level can indicate a risk of Smith-Lemli-Opitz Syndrome, an extremely rare (1:100,000) genetic disorder which can then only be confirmed with an amniocentesis.

A low PAPP-A score in the 1st Trimester could indicate a risk for pre-eclampsia, intrauterine growth restriction (IUGR), or early fetal demise.

PAPP-A is only weakly correlated with the above conditions.

A PAPP-A test is used primarily for Down Syndrome screening.

The primary choice after most prenatal testing is the option to continue or abort pregnancy.

On a rare occasion fetal intervention corrective procedures are possible.

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

If a genetic disease is detected, early diagnosis gives the parents time to research and discuss post-natal treatment and care, or in some cases, abortion.

The Quad test, can also have false positives and false negatives.

When the Quad test yields a score that shows at least a 1 in 270 risk of abnormality, usually the pregnancy is usually normal.

The Quad test, has an 80% sensitivity, so confirmatory amniocentesis testing is required, increasing the risk of miscarriage.

The false-positive rate for the Quad test is greater than 5%.

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.

Diagnostic tests, such as amniocentesis, are considered to be very accurate for defects.

Invasive diagnostic tests have a reported 0.2% error rate.

Higher maternal serum AFP levels indicate a greater risk for anencephaly and open spina bifida.

AFP screening is 80% and 90% sensitive for spina bifida and anencephaly, respectively.

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

Many maternal-fetal specialists do not do an AFP testing, 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.

Performing prenatal tests to determine possible birth defects is mandatory in all states.

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

Amniocentesis has become the standard of care for prenatal care visits for women who are at risk or over a certain age.

Most obstetricians offer patients the AFP triple test, HIV test, and ultrasounds routinely.

Most women meet with a genetic counselor before deciding whether to have prenatal diagnosis.

Obstetricians have an ethical duty to properly inform patients of their options, specifically the availability of screening and prenatal diagnostic testing.

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