Prenatal testing

Prenatal testing is a tool that can be used to detect some

Prenatal

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. Prior information about problems in pregnancy 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.[5]

Prenatal screening

Maternal serum screening

First-trimester maternal serum screening can check levels of free β-

Second-trimester maternal serum screening (

Advances in prenatal screening

Measurement of

A study in 2012 found that the maternal plasma cell-free DNA test was also able to detect trisomy 18 (Edwards syndrome) in 100% of the cases (59/59) at a false-positive rate of 0.28%, and trisomy 13 (Patau syndrome) in 91.7% of the cases (11/12) at a false-positive rate of 0.97%. The test interpreted 99.1% of samples (1,971/1,988); among the 17 samples without an interpretation, three were trisomy 18. The study stated that if z-score cutoffs for trisomy 18 and 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies (this includes all three trisomies: Down, Edwards and Patau).[34]

Prenatal genetic testing

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The goal of prenatal genetic testing is to identify pregnancies at high risk of abnormalities, allowing for early intervention, termination or appropriate management and preparation measures.^[35] Prenatal genetic testing is done by means of different screens and diagnostic tests. A screen informs an individual of the potential for certain abnormalities occurring, whereas, the diagnostic testing is used to confirm/diagnose specific abnormalities exist within the fetus. Prenatal screens are typically less invasive than prenatal diagnostic tests. They come with much lower risk, however, the results are not as definitive as diagnostic tests. Providers often recommend following up with a diagnostic test upon receipt of a positive result from a specific screen.

Medically invasive techniques are those in which a tool is used to access something inside the body. There are varying degrees of invasiveness, depending on what specimen is required to complete the test. The typical blood draw administered by a healthcare professional is one of the most common invasive medical practices.^[36] Since it causes minimal discomfort and there is very low risk associated with the sample collection, a blood draw is considered less invasive. Chorionic villus sampling (CVS) and Amniocentesis are the most invasive prenatal tests because there is greater associated risk and the sample is more difficult to access. These procedures are done via needle insertion into the abdomen in order to collect a sample within the uterus, meaning exceptional care/precision is required.^[37] Prenatal genetic testing can identify various chromosomal abnormalities, autosomal conditions, various birth defects, and some fetal blood disorders.

• Down syndrome (trisomy 21)
• Edwards syndrome
  (trisomy 18)
• Patau syndrome (trisomy 13)
• Turner syndrome (monosomy X)
• Klinefelter (XXY) syndrome
• Trisomy X (XXX) syndrome
• XYY syndrome
• Pallister–Killian syndrome
• Wolf–Hirschhorn syndrome
• Cri-du-chat syndrome
• WAGR syndrome
• DiGeorge syndrome
• Fragile X syndrome

- Prader-Willi/Angelman syndrome

Autosomal recessive conditions occur when both parents pass on a mutation within an autosomal (non-sex) chromosome.^[39]  Some examples of autosomal recessive conditions are:

• Cystic fibrosis
• Sickle cell anemia
• Tay–Sachs disease
• Spinal muscular atrophy
• Autosomal recessive polycystic kidney disease
• Phenylketonuria

Neural tube defects are a type of birth defect that occurs when the neural tube of a fetus does not form/close properly, potentially effecting other systems throughout the body.^[40]  Some examples of neural tube defects are:

• Spina bifida
• Anencephaly
• Encephalocele
• Tethered spinal cord syndrome

Abdominal wall defects are a type of birth defect that occur when the abdominal wall of a fetus does not form properly, potentially effecting other organs throughout the body.^[41]  Some examples of abdominal wall defects are:

• Gastroschisis
• Omphalocele
• Bladder exstrophy
• Cloacal exstrophy
• Ectopia cordis
• Pentalogy of Cantrell
• Body-stalk anomaly

Blood disorders can occur from a negative interaction between the maternal blood and the fetal blood.^[42] An example of a fetal blood disorder is Hemolytic disease of the fetus.

Ultrasound imaging and serum markers as indications for genetic testing

Ultrasound imaging provides the opportunity to conduct a nuchal translucency (NT) scan screening for chromosomal abnormalities such as

Carrier Screening is a general DNA test that uses a blood or cheek swab sample to determine if the parents carry certain genetic conditions. This test can be done anytime, whether the individual(s) are considering starting a family or have already become pregnant. Various types of carrier screens are available that test for progressively more genetic abnormalities. The single gene/condition screen will test for a specific condition, whereas, the expanded carrier screen will test for hundreds of different abnormalities that can be inherited by a fetus. There are also three gene/condition and ethnic specific carrier tests. In the case of a positive test result, further testing is often recommended, as the carrier test only determines if the parent(s) is a carrier, not if the gene has definitively been passed to the fetus.[10]

Placental acellular DNA (pa-DNA)

Placental acellular (fetal cell-free) DNA testing (pa-DNA) allows for the detection of apoptotic placental cells and placental DNA circulating in maternal blood for the noninvasive diagnosis of fetal aneuploidy.

The first, second, combined, and third trimester screens typically consist of an ultrasound (abdominal and/or transvaginal) and maternal blood/serum testing. The ultrasound is used to visually assess the growth, development, and activity of the fetus through imaging observations and measurements. The ultrasound portion of the first trimester screen can include a nuchal translucency screen and a fetal nasal bone determination screen. The available blood tests from the first trimester screen can test for plasma protein A and human chorionic gonadotropin. The second trimester screen looks at specific blood markers, to include the estriol, inhibin and human chorionic gonadotropin hormones and often consists of Alpha-fetoprotein (AFP) screening. Any abnormal results from these screening tests can indicate the possibility of abnormal conditions such as Trisomy 18, Trisomy 21 (Down syndrome), and spina bifida.[13]

Alpha-fetoprotein (AFP)/multiple marker test

The AFP test is often done in the second trimester using the serum from the maternal blood draw. This test looks at a specific protein that is formed in the liver of the fetus and released into the fluid contents of the womb, which is then absorbed into the mother’s blood stream. Multiple determinations stem from the results of AFP testing. Genetically, it can expose chromosomal and neural defects.^[51]

Diagnostic tests

Chorionic Villus Sampling (CVS)

CVS is an invasive diagnostic test that can be done during the first trimester of pregnancy for individuals that are looking to identify or are at higher risk of passing chromosomal abnormalities. A tissue cell sample of the placenta is obtained abdominally via needle or via vaginal insertion of a catheter/syringe into the cervix in combination with ultrasound to guide the procedure. Positive results from CVS require blood testing for confirmation.^[51]

Amniocentesis

Amniocentesis is an invasive diagnostic test that can be done during the second trimester of pregnancy for individuals that are looking to identify or are at higher risk of passing chromosomal and/or neural tube abnormalities. The procedure is typically done via needle, in combination with ultrasound for guidance, to obtain a sample of the amniotic fluid surrounding the fetus.^[51]

Cordocentesis/Percutaneous umbilical blood sampling (PUBS)

PUBS is an invasive diagnostic test that can be done during the second trimester of pregnancy for individuals that are looking to identify or are at higher risk of passing chromosomal and/or blood abnormalities. The demand for cordocentesis tests is diminishing because it has been replaced with CVS and Amniocentesis, which carry less risk. The procedure is typically done via needle into the mother’s abdomen, in combination with ultrasound for guidance, to obtain a blood sample from the umbilical cord of the fetus.^[18]

Prenatal genetic testing analysis techniques

Digital PCR

Recently^[when?], it has been proposed that digital PCR analysis can be conducted on fetal cell-free DNA for detection of fetal aneuploidy. Research has shown that digital PCR can be used to differentiate between normal and aneuploid DNA.^[52]

A variation of the PCR technique called multiplex ligation-dependent probe amplification (MLPA), targeting DNA, has been successively applied for diagnosing fetal aneuploidy as a chromosome- or gene-specific assay.^[53]

Shotgun sequencing

Fetal cell-free DNA has been directly sequenced using shotgun sequencing technology. In one study, DNA was obtained from the blood plasma of eighteen pregnant women. This was followed by mapping the chromosome using the quantification of fragments. This was done using advanced methods in DNA sequencing resulting in the parallel sequencing of the fetal DNA. The amount of sequence tags mapped to each chromosome was counted. If there was a surplus or deficiency in any of the chromosomes, this meant that there was a fetal aneuploid. Using this method of shotgun sequencing, the successful identification of trisomy 21 (Down syndrome), trisomy 18 (Edward syndrome), and trisomy 13 (Patau syndrome) was possible. This method of noninvasive diagnosis is now starting to be heavily used and researched further.^[54]

Other techniques

Microarray analysis, karyotyping, and different genome sequencing techniques are also used to detect abnormalities. Fetal components in samples from maternal blood plasma can be analyzed by genome-wide techniques not only by total DNA, but also by

Diagnostic prenatal testing can be performed by

Non-invasive techniques include examinations of the woman's womb through

One of the major advantages of the non-invasive prenatal testing is that the chance of a false positive result is very low. This accuracy is very important for the pregnant woman, as due to a high sensitivity and specificity of the testing, especially for Down syndrome, the invasive testing could be avoided, which includes the risk of a miscarriage.[56]^[57]

Testing guidelines and qualifying risk factors for invasive testing

The American College of Obstetricians and Gynecologists (ACOG) guidelines currently recommend that anyone who is pregnant, regardless of age, should discuss and be offered non-invasive prenatal genetic screening and diagnostic testing options.^[58] Non-invasive prenatal genetic screening is typically performed at the end of the 1st trimester (11–14 weeks) or during the beginning of the second trimester (15–20 weeks). This involves the pregnant woman receiving a blood draw with a needle and a syringe and an ultrasound of the fetus. Screening tests can then include serum analyte screening or cell-free fetal DNA, and nuchal translucency ultrasound [NT], respectively.^[59] It is important to note that screening tests are not diagnostic, and concerning screening results should be followed up with invasive diagnostic testing for a confirmed diagnosis. Invasive diagnostic prenatal genetic testing can involve chronic villus sampling (CVS) or amniocentesis.^[60] The ACOG recommends genetic screening before pregnancy to all pregnant women planning to have a family.^[61] After comprehensive counseling and discussion that acknowledges residual risks, it is important to respect the patients' right of choosing whether or not to pursue any component of genetic testing.^{[citation needed]}

The following are some reasons why a woman might consider her risk of birth defects already to be high enough to warrant skipping screening and going straight for invasive testing:^[60]

• Increased risk of fetal aneuploidy based on personal obstetric history or family history affected by aneuploidy
• Increased risk for a known genetic or biochemical disease of the fetus
• Maternal transmissible infectious disease such as rubella or toxoplasma
• Parental request in the context of acute parental anxiety or under exceptional circumstances

Patient acceptance

Research was conducted to determine how women felt about noninvasive diagnosis of fetal aneuploid using maternal blood. This study was conducted using surveys. It was reported that eighty-two percent of pregnant women and seventy-nine percent of female medical students view this type of diagnosis in a positive light, agreeing that it is important for prenatal care. Overall, women responded optimistically that this form of diagnosis will be available in the future.^[62]

By pregnancy stage

Pre-conception

Prior to conception, couples may elect to have genetic testing done to determine the odds of conceiving a child with a known genetic anomaly. The most common in the Caucasian population are:^{[citation needed]}

• Cystic fibrosis
• Fragile X syndrome
• Blood disorders such as sickle cell disease
• Tay-Sachs disease
• Spinal muscular atrophy

Hundreds of additional conditions are known and more discovered on a regular basis. However the economic justification for population-wide testing of all known conditions is not well supported, particularly once the cost of possible false positive results and concomitant follow-up testing are taken into account.^[72] There are also ethical concerns related to this or any type of genetic testing.^{[citation needed]}

One or both partners may be aware of other family members with these diseases. Testing prior to conception may alleviate concern, prepare the couple for the potential short- or long-term consequences of having a child with the disease, direct the couple toward adoption or foster parenting, or prompt for preimplantation genetic testing during in vitro fertilization. If a genetic disorder is found, professional genetic counseling is usually recommended owing to the host of ethical considerations related to subsequent decisions for the partners and potential impact on their extended families. Most, but not all, of these diseases follow Mendelian inheritance patterns. Fragile X syndrome is related to expansion of certain repeated DNA segments and may change generation-to-generation.^{[citation needed]}

First trimester

At early presentation of pregnancy at around 6 weeks, early dating ultrasound scan may be offered to help confirm the

Around weeks 11–13, nuchal translucency 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 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 (i.e. detection rate for abnormalities) of 82–87% and a false-positive rate of around 5%.^[73][74]

Cell-free fetal DNA is also available during the first trimester of pregnancy.

Second trimester

The

Third-trimester prenatal testing generally focuses on maternal wellbeing and reducing fetal morbidity/mortality. Group B streptococcal infection (also called Group B strep) may be offered, which is a major cause of neonatal morbidity and mortality. Group B strep is an infection that may be passed to an infant during birth. Vaginal screening for GBS is performed between 34 and 37 weeks of gestational age, so that mothers that are positive for the bacterium can receive treatment before delivery. During the third trimester, some institutions may require evaluations of hemoglobin/hematocrit, syphilis serology, and HIV screening. Also, before delivery, an assessment of fetal position and estimated fetal weight is documented.^[78]

Legislation

In Europe

Prenatal diagnosis (DPN) is permitted throughout Europe, with the exception of Ireland. Eight (8) countries have no legislation on this matter. However, there are differences between states. For instance, in Poland, the deadline for DPN is 22 weeks. In Malta, the Parliamentary Social Affairs Committee specified in its 2005 report that DPN should only be allowed for conditions for which therapeutic options exist. Nevertheless, all countries prohibit DPN for non-medical purposes (such as sex selection), for example.^[79]

In France

Article L2131-1 of the Public Health Code, stemming from the July 2011 bioethics law, states that "prenatal diagnosis refers to medical practices, including obstetric and fetal ultrasound, aimed at detecting, in utero, a particularly severe condition in the embryo or fetus." The law requires that pregnant women receive clear information about these techniques in order to "assess the risk that the embryo or fetus may have a condition that could alter the course or management of the pregnancy.^[80]

Ethical and practical issues

Non-genetic prenatal testing

Parents need to make informed decisions about screening, diagnosis, and any actions to be taken as a result. Many screening tests are inaccurate, so one worrisome test result frequently leads to additional, more invasive tests. If prenatal testing confirms a serious disability, many parents are forced to decide whether to continue the pregnancy or seek an abortion. The "option" of screening becomes an unexpected requirement to decide. See wrongful abortion.

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.^{[citation needed]}

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

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

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

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

Amniotic fluid

Another important issue is the uncertainty of prenatal genetic testing. Uncertainty on genetic testing results from several reasons: the genetic test is associated with a disease but the prognosis and/or probability is unknown, the genetic test provides information different than the familiar disease they tested for, found genetic variants have unknown significance, and finally, results may not be associated with found fetal abnormalities.[82] Richardson and Ormond thoroughly addressed the issue of uncertainty of genetic testing and explained its implication for bioethics. First, the principle of beneficence is assumed in prenatal testing by decreasing the risk of miscarriage, however, uncertain information derived from genetic testing may harm the parents by provoking anxiety and leading to the termination of a fetus that is probably healthy. Second, the principle of autonomy is undermined given a lack of comprehension resulting from new technologies and changing knowledge in the field of genetics. And third, the principle of justice raised issues regarding equal access to emerging prenatal tests.

Availability of treatments

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

Patient education

Researchers have studied how disclosing amniocentesis or chorionic villous sampling (CVS) results on a fixed date versus a variable date (i.e. "when available") affects maternal anxiety. Systematic review of the relevant articles found no conclusive evidence to support issuing amniocentesis results as soon as they become available (in comparison to issuing results on a pre-defined fixed date). The researchers concluded that further studies evaluating the effect of different strategies for disclosing CVS results on maternal anxiety are needed.^[83]

Concerns from disability rights activists and scholars

Disability rights activists and scholars have suggested a more critical view of prenatal testing and its implications for people with disabilities. They argue that there is pressure to abort fetuses that might be born with disabilities, and that these pressures rely on eugenics interests and ableist stereotypes.^[84] This selective abortion relies on the ideas that people with disabilities cannot live desirable lives, that they are "defective," and that they are burdens, while disability scholars argue that "oppression is what's most disabling about disability." Marsha Saxton suggests that women should question whether or not they are relying on real, factual information about people with disabilities or on stereotypes if they decide to abort a fetus with a disability.^[85]

Societal pressures

Amniocentesis has become the standard of care for prenatal care visits for women who are "at risk" or over a certain age. The wide use of amniocentesis has been defined as consumeristic.

August in 2023 Iranian government banned import and manufacture of tests kits required for first screening trimester tests, it will plague the population according to society of medicine in genetic انجمن ژنتیک پزشکی ایران [fa].^[88] Iranian state welfare organization had a genetics condition program since 1997.^[89]

See also

• Amniocentesis
• Amniotic stem cell bank
• Amniotic stem cells
• Chorionic villi
• Genetic counseling
• Newborn screening

Notes and references