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Grand Rounds
CMECNE

Does Noninvasive Screening Result in Fewer Miscarriages When Compared to Amniocentesis?

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Learning Objectives and CME/Disclosure Information

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. Discuss the reason for a study to compare fetal loss after NIPS vs invasive testing
2. Describe the results of this RCT with respect to miscarriage rate differences between the NIPS group and the invasive testing group

Estimated time to complete activity: 0.25 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires faculty, planners, and others in control of educational content to disclose all their financial relationships with ineligible companies. All identified conflicts of interest (COI) are thoroughly vetted and mitigated according to PIM policy. PIM is committed to providing its learners with high quality accredited continuing education activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.

The PIM planners and others have nothing to disclose. The OBG Project planners and others have nothing to disclose.

Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.

Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

Method of Participation and Request for Credit

Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from Aug 27 2018 through Jan 25 2023, participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.2 contact hours.

Read Disclaimer & Fine Print

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

Take a post-test and get CME credits

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Related ObG Topics:

Practical info on evidence based medicine for your women's healthcare practice
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?

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Computer System Requirements

OBG Project CME requires a modern web browser (Internet Explorer 10+, Mozilla Firefox, Apple Safari, Google Chrome, Microsoft Edge). Certain educational activities may require additional software to view multimedia, presentation, or printable versions of their content. These activities will be marked as such and will provide links to the required software. That software may be: Adobe Flash, Apple QuickTime, Adobe Acrobat, Microsoft PowerPoint, Windows Media Player, or Real Networks Real One Player.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information
presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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