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

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 instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Faculty: Susan J. Gross, MD, receives consulting fees from Genoox, Inc., 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 Aug 27 2019, 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.

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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

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