BACKGROUND AND PURPOSE: 

• NIPS has a high sensitivity for the detection of Down syndrome, without the risk of miscarriage 
  • Reduced miscarriage rates compared to invasive testing is theoretical as there has not yet been a ‘head to head’ RCT to determine if this is indeed the case 
  • NIPS is a screening test and will not detect the same spectrum of disorders when compared to diagnostic testing  
• Malan et al. (JAMA, 2018) compared miscarriage rates following invasive procedures in the context of positive cfDNA test results versus immediate invasive testing procedures in pregnancies with high trisomy 21 risk

METHODS: 

• Randomized open-label multi-center clinical trial (RCT) 
• Inclusion criteria  
  • Women with pregnancies at risk of trisomy 21  
    • ‘Screen positive’ risk defined as being between 1/5 to 1/250 following standard combined first trimester screening or sequential screening  
  • Maternal age: ≥18 years 
  • Gestational age: 11 to 18 weeks  
• Exclusion criteria 
  • NT >3 mm | PAPPA <0.3 MoMs | β hCG >5 MoMs   
  • Ultrasound (first trimester): Fetal anomalies or vanishing twin  
  • Genetics: Known prior parental balanced translocation  
• Patients were randomized to either 
  • NIPS testing followed by invasive testing depending on test result  
  • Immediate invasive testing (amniocentesis or chorionic villus sampling) 
    • Invasive testing: CVS or amniocentesis  
• Power analysis 
  • To observe a decrease in miscarriage from 1.5% to 0.5% between the invasive and cfDNA testing groups, respectively, 1250 patients per group (1-sided α=.05 and 80% power) 
• Primary outcome: Miscarriage <24 weeks 
• Secondary outcomes  
  • Number and percentage of invasive procedures | Performance characteristics of NIPS testing | Time interval between blood sample receipt and result availability | Diagnosis of chromosomal abnormalities  
• Post hoc outcomes 
  • IUFD | Termination of pregnancy | Live birth | Perinatal death

RESULTS: 

• 1034 NIPS group | 1017 invasive testing  
  • Mean age: 36.3 (SD, 5.0) years 

Primary outcome- miscarriage rate 

• The miscarriage rate was not significantly different between NIPS group (0.8%) and invasive group (0.8%); P = .47 

Secondary outcomes 

• Invasive testing 
  • 8.3% of women in NIPS group vs 76.5% in the invasive group  
• Chromosomal detection rates were lower in the NIPS group (P=.01) 
  • 28 (2.8%) of NIPS group and and 49 (5%) of the invasive testing group had chromosomal abnormalities  
    • Risk difference, −2.23%; 95% CI −3.93% to −0.54%  
    • 1 (0.1%) of anomalies in the NIPS group and 11 (1.1%) in the invasive testing group were not trisomy 21 (P=.003) 
  • Anomaly in the NIPS group was a tetrasomy 12p with multiple anomalies on 2nd trimester ultrasound  

Post hoc analysis  

• When comparing women who did vs did not have an invasive procedure, there was no difference in miscarriage rate (P=.41)  
  • NIPS group: 0.8% 
  • Invasive testing group: 0.9%  
• There were no differences in other perinatal outcomes

CONCLUSION: 

• Immediate invasive testing did not introduce miscarriage risk to pregnancies with high trisomy 21 risk 
• In this cohort, 1.5% additional chromosomal anomalies were found that were not detected in the NIPS arm (using standard karyotyping)  
  • Microarray would have detected even more significant anomalies  
    • 6% additional chromosomal abnormalities would be detected in fetuses with fetal anomalies
    • 0.5% to 2.5% additional chromosomal abnormalities would be detected in fetuses of advanced maternal age mothers or positive combined maternal serum screening  
• The authors acknowledge that the study may not have been adequately powered to identify clinically significant differences in fetal loss rates  
  • 17% of women declined randomization  
  • 24% of women randomized to invasive testing declined testing

Learn More – Primary Sources: 

Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21

Related ObG Topics:

cfDNA vs. Routine Screening – How Do They Compare?

What is the Best Strategy for Fetal Aneuploidy Screening?

SMFM Guidance – The Role of Prenatal Ultrasound and NIPT 

How Accurate is NIPT as a Screening Test for Chromosomal Aneuploidies?