Non-Invasive Prenatal Screening

NIPThe addition of non-invasive prenatal screening (NIPS), or cell free DNA (cfDNA) testing, to the prenatal testing menu has brought increased sensitivity and specificity to prenatal screening for the common trisomies (trisomy 21, trisomy 18 and trisomy 13) compared with traditional prenatal screening tests1. However, it cannot be overstated that NIPS is NOT a diagnostic test. False positives and false negatives can and do occur.  Why?  Here are some examples:

  • The source of fetal cell free DNA present in the maternal bloodstream is thought to be primarily placental in origin2.  Confined placental mosaicism describes the situation when a chromosomal abnormality is present only in the cells of the placenta and NOT in the cells of the fetus. Therefore, a false positive NIPS result can occur in cases of confined placental mosaicism, for example trisomy 21 cells in the placenta that are not present in the fetus.
  • Spontaneous loss of one embryo occurs in 30 to 40 percent of twin pregnancies3 (vanishing twin). A high percentage of vanishing twins are chromosomally abnormal. A false positive NIPS result can result when cells from a chromosomally abnormal vanishing twin are circulating in the maternal blood stream.
  • Approximately three to six percent of cell-free DNA circulating in the maternal blood stream is fetal in origin4 – the remainder is cell-free maternal DNA. If the amount of fetal cfDNA in the maternal blood sample is insufficient, the maternal cfDNA can “mask” the presence of a fetal chromosome abnormality, resulting in a false negative result.

Equally important to keep in mind is the concept of positive predictive value (PPV). The PPV of a screening test refers to the chance that the condition is actually present given the incidence of the condition in the population. In other words, a positive screening result is more likely to be a true positive as the condition becomes more prevalent in the population being screened. Conversely, a positive screening result is less likely to be a true positive as the condition becomes less prevalent in the population being screened.

This article on non-invasive prenatal screening (NIPS) was written by our genetic counselor, Cheryl Dickerson.

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As illustrated in the table below, there is a 98 percent chance that a “positive” or “high risk” trisomy 21 NIPS result in a 40-year-old pregnant woman is a true positive while there is less of a chance (75 percent) that a “positive” trisomy 21 NIPS result in a 20-year-old pregnant woman is a true positive. Why? Because the incidence of trisomy 21 is higher in the pregnancies of 40 year olds compared with 20 year olds. Furthermore, the PPVs for trisomy 18 and trisomy 13 are inherently lower than the PPV for trisomy 21 because the prevalence of trisomy 18 and trisomy 13 is lower than trisomy 21.

Condition

2nd TM incidence
in pregnancy of
40 year old

Positive NIPS PPV
(chance that pregnancy is
actually affected)

2nd TM incidence
in pregnancy of
20 year old

Positive NIPS PPV
(chance that pregnancy is
actually affected)

Trisomy 21

1/71

98%

1/1,117

75%

Trisomy 18

1/267

84%

1/4,215

25%

Trisomy 13

1/809

50%

1/12,795

6%

*based on estimates of maternal age related risks of the common trisomies and PPVs of NIPS5

This table illustrates why it is so important that pregnant women receive accurate pre- and post-test counseling about NIPS. Yes, NIPS is an important technological advancement in providing better prenatal screening for the common trisomies, but it is not a replacement for testing through CVS or amniocentesis for a definitive diagnosis during pregnancy.

This article was written by Cheryl Dickerson, MS, CGC, certified genetic counselor with WakeMed Physician Practices - Maternal Fetal Medicine.

References
1. Norton ME at al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med 2015 Apr 1. [Epub ahead of print]
2. Bianchi DW. Circulating fetal DNA: its origin and diagnostic potential—a review. Placenta. 2004;25(Suppl A):S93–S101.
3. Dickey RP et al. Spontaneous reduction of multiple pregnancy: Incidence and effect on outcome. Am J Obstet Gynecol 2002;186:77-83.
4. Lo YM et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350(9076):485-487.
5. Resources for Health Care Professionals, http://mombaby.org/index.php?c=2

Current Professional Society Recommendations regarding NIPS