Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology

Submitted by Anna David PhD FRCOG

Director of the Institute for Women’s Health
Professor and Consultant in Obstetrics and Maternal-Fetal Medicine
Honorary Professor of Fetal Medicine, KU Leuven

 

Are you carrying out trials focused on maternal or fetal surgery?

MFAET version 1.0 is a new terminology to define and grade maternal and fetal Adverse Events to monitor therapeutic safety in pregnancy clinical trials. It includes 12 new maternal & 19 fetal Adverse Event definitions which are adopted by MedDRA, the Medical Dictionary of Regulatory Activities. It can be used to monitor safety in clinical trials but also to categorise outcomes in historical and prospective observational studies.

The paper describing the new terminology can be found HERE.

Further resources describing how to use the terminology can be found HERE.

 

How did we develop MFAET?

1. We identified existing severity grading for pregnant AEs & definitions of severe conditions relevant to maternal & fetal clinical trials eg guidelines and statements from RCOG, ACOG, NICE, RANZCOG, DGGE, WHO, SOGC, BAPM, ISUOG, CPS, SMFM & FIGO

2. Existing terminology was limited for maternal AEs and only had two fetal AEs, poor fetal growth & fetal death:
   See CTCAE*: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf
   Division of AIDS: https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables
   *CTCAE = Common Terminology Criteria for Adverse Events.

There was a major gap in the tools for maternal and fetal translational medicine research.

3. The Steering Group (experts in fetal medicine, fetal surgery, neonatology and pharma) met in May 2015. Maternal AE definitions & severity grading were developed using CTCAE generic grading 1-5 eg for haemorrhage, PPROM, chorioamnionitis, anaemia, gestational hypertension, preeclampsia, eclampsia, preterm labour, puerperal infection, retained placenta and amniotic fluid embolus.

4. For fetal AEs we developed a generic severity grading system 1-5. We considered the potential impacts of maternal or fetal therapies on fetal organ systems. Effects of maternal AEs on the fetus were also included. We adapted AE definitions from existing clinical definitions.

5. Fetal AEs must be diagnosable in utero eg with USS/MR imaging, CTG/fetal heart rate monitoring & they must have potential to cause a detrimental effect to the fetus.
   AEs that only manifest after birth were considered to be neonatal AEs, even if they had originated in utero.

6. Some fetal AEs relate to specific organs/systems eg abnormalities of the gastrointestinal, renal, brain or musculoskeletal systems detected by imaging.
   Other fetal AEs are disorders of fetal movement, cardiac dysfunction, poor fetal growth & fetal fluid collection.

We also graded fetal heart rate abnormalities eg bradycardia & tachyarrhythmia, fetal neoplasm & general fetal structural abnormalities.
Definitions were developed specifically for AEs related to fetal interventions eg fetal intraoperative injury, fetal procedural haemorrhage.

7. Patients & public groups co-developed MFAET with recommendations in pregnancy clinical trials to assess psychological impact of fetal interventions on the mother & capture data on subsequent fertility: SHINE, CDH-UK, Twins Trust, Antenatal Results and Choices, SANDS.

8. We integrated the fetal AE terms with existing MedDRA terms, hierarchy, structure & function.

9. Maternal and fetal AEs underwent a 2-stage international Delphi consensus across Europe, US & Canada, South America, Middle East, Asia, Australasia & Africa of clinicians, & patient groups.

 

Thanks to funding from Wellcome Trust, EPSRC, European Commission, NIHR, German Research Foundation, GOSH Charity & EGA Hospital Charity

 

For further information see: https://www.ucl.ac.uk/news/2021/oct/new-guidelines-improve-pregnancy-trials-will-pave-way-novel-therapies-women-and-babies