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

OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.

Clinical Assessment of Fetal Well-Being and Fetal Safety Indicators.

Delivering safe clinical trials of novel therapeutics is central to enable pregnant women and their babies to access medicines for better outcomes. This review describes clinical monitoring of fetal well-being and safety. Current pregnancy surveillance includes regular antenatal checks of blood pressure and urine for signs of gestational hypertension. Fetal and placental development is assessed routinely using the first-trimester "dating" and mid-trimester "anomaly" ultrasound scans, but the detection of fetal anomalies can continue throughout pregnancy using targeted sonography or magnetic resonance imaging (MRI). Serial sonography can be used to assess fetal size, well-being, and placental function. Carefully defined reproducible imaging parameters, such as the head circumference (HC), abdominal circumference (AC), and femur length (FL), are combined to calculate an estimate of the fetal weight. Doppler analysis of maternal uterine blood flow predicts placental insufficiency, which is associated with poor fetal growth. Fetal doppler analysis can indicate circulatory decompensation and fetal hypoxia, requiring delivery to be expedited. Novel ways to assess fetal well-being and placental function using MRI, computerized cardiotocography (CTG), serum circulating fetoplacental proteins, and mRNA may improve the assessment of the safety and efficacy of maternal and fetal interventions. Progress has been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. A new system for improved safety monitoring for clinical trials in pregnancy, Maternal and Fetal Adverse Event Terminology (MFAET), describes 12 maternal and 18 fetal adverse event (AE) definitions and severity grading criteria developed through an international modified Delphi consensus process. This fills a vital gap in maternal and fetal translational medicine research.

Improving Development of Drug Treatments for Pregnant Women and the Fetus.

The exclusion of pregnant populations, women of reproductive age, and the fetus from clinical trials of therapeutics is a major global public health issue. It is also a problem of inequity in medicines development, as pregnancy is a protected characteristic. The current regulatory requirements for drugs in pregnancy are being analyzed by a number of agencies worldwide. There has been considerable investment in developing expertise in pregnancy clinical trials (for the pregnant person and the fetus) such as the Obstetric-Fetal Pharmacology Research Centers funded by the National Institute of Child Health and Human Development. Progress has also been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. Innovative methods to model human pregnancy physiology and pharmacology using computer simulations are also gaining interest. Novel ways to assess fetal well-being and placental function using magnetic resonance imaging, computerized cardiotocography, serum circulating fetoplacental proteins, and mRNA may permit better assessment of the safety and efficacy of interventions in the mother and fetus. The core outcomes in women's and newborn health initiative is facilitating the consistent reporting of data from pregnancy trials. Electronic medical records integrated with pharmacy services should improve the strength of pharmacoepidemiologic and pharmacovigilance studies. Incentives such as investigational plans and orphan disease designation have been taken up for obstetric, fetal, and neonatal diseases. This review describes the progress that is being made to better understand the extent of the problem and to develop applicable solutions.