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Cells trafficking between the maternal and fetal compartments was first noted in 1893 by Schmorl. The ability to quantify and analyze these fetal cells using cell sorting and polymerase chain reaction was not developed until approximately 1 century later. Clinical applications and commercial availability of advanced technologies, now commonly known as noninvasive prenatal testing (NIPT) or cell-free fetal DNA testing, then followed in October 2011.
The advent of NIPT just a few years ago has changed the landscape of prenatal diagnosis significantly for genetic abnormalities. In this issue, Larion et al report the effect of NIPT on traditional aneuploidy screening and diagnostic testing by evaluating a 51-month study period that bracketed the introduction of NIPT (35 months before and 16 months after). Uptake of NIPT increased by 55% over the course of the study period, with a shift from first-trimester screening to NIPT. A concomitant decrease was noted in average monthly chronic villus sampling and amniocentesis procedures by 77.2% and 52.5%, respectively. Although NIPT uptake varies by region and patient personal demographics, it is abundantly clear that there is a substantial paradigm shift in prenatal aneuploidy screening.
NIPT is attractive to both the patient and practitioner in many ways. Earlier and improved detection of aneuploidy at 10 weeks’ gestational age surpasses the 85-90% detection rate of traditional first-trimester screening with nuchal translucency and serum analytes from 11-14 weeks of gestation. Cell-free fetal DNA screening results in lower screen positive rates and subsequent decrease in invasive procedures and patient anxiety, as Larion et al described. In addition to the detection of the common fetal trisomies, NIPT can offer information on sex chromosome disorders and fetal sex in at-risk disorders, such as congenital adrenal hyperplasia. In addition, fetal Rhesus status can also be effectively evaluated to avoid the need for anti-D immunoglobulin. Although the American College of Obstetricians and Gynecologists currently recommends NIPT only in high-risk patients, its widespread roll-out and aggressive marketing has led to NIPT becoming almost a part of the “routine first-trimester prenatal panel.” Recent studies are supportive of this enthusiasm.
Because of its widespread introduction and acceptance, the ideal role of NIPT in routine obstetrics care remains to be defined. One major concern is the process of integration of NIPT into the preexisting clinical armamentarium of prenatal diagnosis. In California, for example, aneuploidy screening by sequential integrated screening has been offered successfully by a state-wide prenatal diagnosis program ( Figure ). Incorporation of NIPT into this program has led to confusion for the patients and practitioners regarding whether tests are to be ordered simultaneously, sequentially, or exclusive of each other. Although the state program is clear as to how NIPT should be used, it remains less clear to clinicians. In cases in which simultaneous testing results in discordant outcomes between NIPT and traditional aneuploidy screening, the decision regarding invasive diagnostic testing becomes even more difficult.
Pretest genetic counseling is essential to ensure patient understanding of limitations and benefit of NIPT before the test is ordered. Patients and providers both must be informed of these important points: (1) the detection rate is superior to other prenatal screening tests; (2) the test is not diagnostic; (3) diagnostic testing is recommended to confirm a positive NIPT result, and (4) NIPT is not as comprehensive as invasive testing. Patients should also be aware that sensitivity and specificity of NIPT testing vary between trisomy 21 and the other autosomal aneuploidies. For example, the fetal fraction is higher in maternal plasma when the fetus has trisomy 21 and is lower when the fetus has trisomy 18, 13, or monosomy X. This difference in fetal fractions (which are noted in maternal weights, ethnic background, smoking, and fetal age) alters the diagnostic sensitivity and specificity of the test for the different aneuploidies. Recent reports suggest that inconclusive results or uninterpretable results may be more concerning than first thought (personal communication from Dr Norton to Dr Platt).
Genetic counseling sessions, which are an important adjunct to prenatal testing, have been noted therefore to be more time-intensive than before NIPT introduction, because patient knowledge gaps require more intensive education during these sessions. In the routine busy obstetrics practice, however, thorough genetic counseling is almost impossible and generally unavailable. With the rapid expansion of genetic testing, commercial laboratories with cytogenetic laboratories for a long time have employed genetic counselors. More recently companies that are entering the market for carrier testing have recognized this deficiency in counseling, and many have begun to employ large numbers of genetic counselors to help develop self-education online modules and tools to support the market and to be available to patients with questions regarding their test results. All companies that offer NIPT products have also recognized this need to provide genetic counseling but will likely require increased staffing.
Because patients gain early reassurance regarding the absence of aneuploidy, the role of comprehensive first-trimester ultrasound screening will also evolve. An early anatomic survey may provide information such as acrania, cystic hygroma, or limb-body wall defects that NIPT alone will not detect. The recent National Institute of Child Health and Human Development Fetal Imaging Workshop states that evaluation for early detection of these anomalies is “reasonable” but does not consider routine anatomic evaluation a requirement in the first trimester. We believe that as traditional first-trimester aneuploidy screening fades away with the increase in NIPT, first-trimester ultrasound screening should not be abandoned but rather should evolve into early detailed anatomic surveys.
Traditional first-trimester screening also offered information about maternal serum analytes that may serve as markers of uteroplacental insufficiency. Alterations in levels of pregnancy-associated plasma protein-A and human chorionic gonadotropin had been thought of as potential markers for the need for growth and antenatal surveillance but have not been shown to improve perinatal outcomes. As the obstetrics community develops newer and more effective screening modalities for uteroplacental insufficiency (such as maternal serum angiogenic factors, urine congophilia, and metabolomics or genomic markers), there will be even less use for the current first-trimester serum analytes. Second-trimester maternal serum alpha-fetoprotein will also increasingly be replaced by anatomic survey ultrasound scans, given the accuracy of high-resolution ultrasound scanning in the detection of both neural tube and ventral wall defects.
Furthermore, limited testing for copy number variants (CNVs), such as microduplications and deletions, has become available commercially by specific companies. Microdeletions that are available commercially for evaluation by NIPT are DiGeorge (chromosome 22q11.2 deletion), Angelman/Prader-Willi (1p36 deletion), Wolf-Hirschhorn, Cri-du-chat (5p-), Miller-Dieker, and Phelan-McDermid syndromes. Low prevalence of these rare CNVs in vitro affects sensitivity and specificity. False-positive results are of a real and significant concern, as evidenced by our own personal experience of 2 Cri-du-chat and 1 Angelman false-positive results over the past year, with no true positive tests. Clearly, the low prevalence of the microdeletions accounts for this lack of any positive tests, but the screen positive rate is a true concern, considering that no actual prospective clinical trial has been reported in these laboratory-developed tests not requiring Food and Drug Administration approval. Currently, microdeletions are included in testing as an opt-out option and are reported as “incidental findings.” We believe, therefore, that prospective clinical trials are needed before full deployment of this testing in the clinical armamentarium. However, if trials confirm its utility, we look forward to the development of other markers of syndromes and diseases that can be identified noninvasively through cell-free fetal DNA.
At a birds-eye level, providers must take into account the impact of NIPT on cost of health care. Current costs for NIPT range from $500-2700 in the United States (although the cost is much less in the California state program), and £400-£900 in the United Kingdom. Cost-effectiveness model analysis of NIPT vs current screening in the United Kingdom showed that NIPT is likely to produce more favorable outcomes, but at greater cost, when used as a first-line test. As a contingent screen, however, NIPT would be cost-neutral or cost-saving. Furthermore, NIPT as a screening tool that requires a confirmatory amniocentesis is cost-effective and leads to far fewer losses of normal pregnancies, compared with NIPT use as a diagnostic tool. A cost-model to evaluate its use in high-risk population showed significant clinical and cost advantages.
A discussion regarding the business of NIPT must also address the confusing nomenclature. There are very few incidences in medicine of tests that are referred to almost exclusively by brand names in the clinical setting. Patients and providers often replace “NIPT” and “cell-free fetal DNA” with specific brand names, again as a result of marketing techniques. We believe that it is important for both patients and providers to step off the bandwagon and objectively assess the technology and applications.
The impact of this paradigm shift on the training of future Maternal-Fetal Medicine practitioners should also be considered. The significant decrease in invasive procedures will result in fewer individuals who are trained adequately to provide services such as chorionic villus sampling and who will maintain competence and proficiency adequately. In the state of California, dedicated prenatal diagnosis centers are required to prove adequate annual cases of chronic villus sampling and amniocentesis procedures. The result of the decrease in procedures in that state has already led to a lowering of the number of annual cases to maintain proficiency. This lowering of the required number of procedures must be monitored against the number of adverse outcomes. Nonetheless, we argue that this credentialing process should be adopted universally for the safety of patients because these procedures become increasingly marginalized, where the old “see one, do one, teach one” is no longer an acceptable approach.
As we continue forth in this era of NIPT, providers must continue to exercise cautious and informed enthusiasm for the test. Providers must be up to date on the technology and must provide the avenue for their patients to understand fully the new testing schema. They must be prepared to answer questions from their highly educated and internet-savvy patients. Further clinical trials are being demanded to evaluate the use of NIPT in low-risk populations and evaluation of CNVs. The role of detailed first-trimester ultrasound screening must also be reevaluated simultaneously. Clinical algorithms for aneuploidy screening must be revised by our national organizations to incorporate NIPT into the current screening. NIPT is one of those advances that can truly be called a ‘game changer.’
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