A person can undergo various genetic tests with different intended targets. With the development of knowledge of human genetics, our technological capabilities for executing various genetic tests expanded rapidly over the last few decades. In pregnancy, the main categories of genetic tests are the following.
1) Tests focused on screening for genetic disorders in the developing fetus - prenatal genetic testing
2) Informative DNA tests of the parent, targeted at discovering genealogical information and possible predispositions and health-related traits.
Nowadays, pregnant individuals can undergo invasive or non-invasive procedures to analyze the genetic information of the fetus developing in their bodies before they are born – i.e., prenatally. The goal of prenatal genetic testing is to screen for fetal genetic diseases or to identify the absence of genetic risk factors and help early assessment of the risk level of the individual's pregnancy. If a screening test returns a positive result, a diagnostic test must be done to confirm or disprove the preliminary suspicion. This helps pregnant individuals, their partners, and their healthcare providers to prepare for the most likely eventualities and discuss their options. [1]
At the same time, there is a different category of DNA tests targeted at analyzing the genetic information of the pregnant person themselves. This is the DNA testing that anyone can get to learn more about their genetic make-up. Many consumer genomics companies offer those tests worldwide that usually consist of a self-sampling home kit for collecting saliva. However, this testing cannot provide information about the genetic information of the unborn child, as it only analyzes the parent's genome. It is possible to get such a test done during pregnancy and outside of it. No known risks are associated with getting a home genetic test during pregnancy. Macromo doesn't offer diagnostic testing for unborn children, only genetic tests that measure the genetic risks of the person who provides the sample.
Below, various aspects of prenatal diagnostic tests are discussed - such as what options for prenatal genetic tests are there, how they are administered, and their respective benefits and risks.
Various methods are available for detecting fetal genetic abnormalities depending on the stage of pregnancy. Although early recognition may indeed lead to better outcomes, confirmation of diagnoses at an earlier gestational age is complicated. Generally, the tests for fetal genetic abnormalities can be divided into the categories of screening tests and diagnostic tests. Below are listed the respective specific methods, their indications and limitations, and the timeframe for their use in pregnancy. One of the important messages to bear in mind is that all pregnant women should have the option to pursue prenatal genetic screening tests, regardless of when they present for prenatal care.
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Although the actual practices differ from country to country, there are, in general, a few screening options available to detect genetic abnormalities before birth. These can be divided into those that analyze the blood (or, more specifically, serum) of the carrying parent or those that analyze fetal DNA.
The First Trimester Screening (FTS) is a traditional serum-based method in which the levels of various markers are measured. The testing is done together with an ultrasound examination. It is available approximately between weeks 11 and 14 of gestational age (i.e., counting from the last menstrual period). The combined FTS has a relatively high sensitivity (ca. 87%) and specificity (ca. 97%) for detecting extra or missing chromosomes, which cause disorders such as Down syndrome. [2] Waiting for the results of the FTS usually does not take much longer than a few days. In the second trimester, one of the available options is the 'quad screen' (available between weeks 15-23). It is again a serum-based method in which the levels of specific markers in the blood are obtained and used to assess the risk of Down syndrome or other chromosomal abnormalities, as well as structural defects (open neural tube defects) of the fetus. Clinicians may use all of the results in a combined analysis, which may increase the precision of the final assessment.
A completely different category of prenatal tests is the non-invasive, DNA-based methods. This approach is based on the discovery of free fetal DNA in maternal blood by Lo et al. [3]. This means that there are pieces of DNA from the cells of the unborn child or the placenta (which shares its genetic information with the fetus) that, when combined in a meaningful manner, may provide invaluable knowledge of the fetal genomic characteristics. Nowadays, it is possible to analyze the fetal genome from a blood draw done after week 9. Moreover, this analysis of cell-free DNA (cfDNA), also known as NIPS (non-invasive prenatal screening), is currently the most sensitive screening test for Down syndrome and is comparable with the traditional serum-based methods in detecting other chromosomal abnormalities. [4] The results of NIPS take 1-2 weeks, and the option to not learn the fetal sex is still available for the parents, even while being provided information about potential problems with the sex chromosomes. [5]
Whenever a screening test, be it a serum-based method, NIPS, or an ultrasound scan, returns a positive result, or there are other risk factors present, it may warrant a diagnostic test in order to either confirm or disprove the suspicion of an abnormality. Diagnostic tests differ from screening tests by obtaining fetal DNA directly from the fetal tissue. Their approach consists of a more reliable way of acquisition of samples for analysis. Nevertheless, as they may pose a risk to the unborn child, it is always up to the parent's decision whether or not to pursue the diagnostic test. Chorionic villus sampling (CVS) and amniocentesis are the two most commonly used methods.
CVS is a method in which a small hollow tube/needle is inserted either through the cervix (transcervical approach) or through the abdomen (transabdominal approach). In either case, ultrasound is used to guide the process. Through this tube, the physician obtains placental tissue for genetic analysis. CVS is usually done in the first trimester, after week 10 of gestation. Although CVS can also be performed later, after week 14, amniocentesis is the method of choice due to lower technical difficulty. [6]
In amniocentesis, a needle is used to extract amniotic fluid from the uterus under the guidance of an ultrasound. In the small amount of amniotic fluid that is removed, there are fetal cells containing DNA for genetic analysis. It is possible to conduct amniocentesis after week 11 of gestation, but later timing is preferred for safety reasons – usually between weeks 15 and 18. [7]
An essential aspect of diagnostic testing is the safety of the fetus and the carrying individual. Studies have shown that CVS, as well as amniocentesis, may slightly increase the chance of complications of pregnancy and miscarriage. The fetal loss rate following a CVS is minimal, around 0.6%. [6] It has been estimated that early amniocentesis is not as safe as second-trimester amniocentesis, primarily due to increased pregnancy loss and limb abnormalities. [8] Nevertheless, amniocentesis still carries a very small risk of pregnancy loss caused by the procedure, around 0.2-0.3 percent. [7] It may be challenging to isolate the exact cause of pregnancy loss, which hinders the analysis done in the studies investigating prenatal diagnostic testing and its risks. It remains vital for the prospective parent to discuss the options with the prescribing physician to be able to make an informed decision.
The information obtained through prenatal testing is of great value to healthcare providers and prospective parents. Learning about a fetus's possible genetic abnormalities may help prepare for the possible trajectories one might choose or the scenarios that are the most likely to happen. Early detection of potential complications enables preparation on a psychological and social level.
The genetic tests differ in whether they test the DNA of an unborn child or the parent. There are multiple ways to learn more about the genome of a developing fetus. Screening options are the less invasive first step. Diagnostic tests come into play when there are risk factors or suspicion. At-home genetic testing can be used to screen for health issues in parents but not in an unborn child. The results of such DNA tests are not affected by pregnancy. Nevertheless, some rare diseases can develop in children based on mutations that can be inherited from the parents. Hence, taking a genetic test before conceiving as a way of prevention is advisable.
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[1] Jelin AC, Sagaser KG, Wilkins-Haug L. Prenatal Genetic Testing Options. Pediatr Clin North Am. 2019;66(2):281-293. doi:10.1016/j.pcl.2018.12.016
[2] Li SW, Barrett AN, Gole L, et al. The assessment of combined first trimester screening in women of advanced maternal age in an Asian cohort. Singapore Med J. 2015;56(1):47-52. doi:10.11622/smedj.2015009
[3] Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997;350(9076):485-487. doi:10.1016/S0140-6736(97)02174-0
[4] Gil MM, Galeva S, Jani J, et al. Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of The Fetal Medicine Foundation results and meta-analysis. Ultrasound in Obstetrics & Gynecology. 2019;53(6):734-742. doi:10.1002/uog.20284
[5] Goldwaser T, Klugman S. Cell-free DNA for the detection of fetal aneuploidy. Fertility and Sterility. 2018;109(2):195-200. doi:10.1016/j.fertnstert.2017.12.019
[6] Ghidini A. Chorionic villus sampling. UpToDate. Published January 20, 2021. Accessed July 31, 2022. https://www.uptodate.com/contents/chorionic-villus-sampling
[7] Ghidini A. Diagnostic amniocentesis - UpToDate. UpToDate. Published September 2, 2021. Accessed July 31, 2022. https://www.uptodate.com/contents/diagnostic-amniocentesis
[8] Alfirevic Z, Navaratnam K, Mujezinovic F. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev. 2017;2017(9):CD003252. doi:10.1002/14651858.CD003252.pub2