Key endpoints and definitions for collection of data on outcomes using a ‘tiered’ approach

This list of pregnancy, birth and infant endpoints was suggested for the purpose of optimizing and harmonizing pregnancy safety data across studies and settings. Endpoints and their definitions were aligned with the WHO inter-departmental task team work to improve maternal and newborn health in low- and middle- income countries (LMICs).

Endpoints were grouped into “tiers” (core; expanded; comprehensive), guided by two main factors:

the relative clinical/public health importance of the endpoint, and
the feasibility and resource intensity of collecting data of reasonable quality on the endpoint.

The goal of the tier groupings is to help guide the minimum pregnancy data that should ideally be collected, acknowledging that it will not be feasible to collect some of these pregnancy-related endpoints outside of clinical trial settings.

For all endpoint and exposure/predictor data:

basic information on the data source(s) should also be collected (e.g. electronic versus paper, from routine clinical sources versus from participants, retrospectively versus prospectively, data based on ultrasounds or other data, etc.).
actual numeric dates and endpoint values should be collected rather than just categorial data (e.g. date and gestational age at delivery rather than simply term/preterm).

Endpoint collection and ascertainment is expected to vary between studies, because of data collection approach, study design, feasibility, resources, and the goals of the projects.

As both sex at birth as well as gender identity can intersect to influence health outcomes, it is important to ensure that data are reported on both sex at birth and gender identity in pregnant and breastfeeding populations (including transgender men and non-binary people who are assigned female at birth and able to become pregnant) in medicines development research.

Table 1. Core endpoints

Birth outcomes	Maternal outcomes	Neonatal/infant outcomes
Stillbirth*	Mortality during pregnancy, labour and delivery, and in facility	Neonatal death (in facility)
Preterm birth <37 weeks*
Very preterm birth <32 weeks*
Birthweight
Small for gestational age (SGA) (<10th percentile) if possible*
Congenital anomalies reported at birth (through routine reporting)
Miscarriage (any miscarriage <28 weeks; early miscarriage <20 weeks)* Note: while miscarriage is an important endpoint, it is often under-reported and retrospective collection of sufficient-quality data on miscarriage is often not feasible

*Dating/estimated gestational age is required when defining these endpoints. Perform fetal ultrasound for dating where possible; and record whether ultrasound was available for pregnancy dating (and which data were used to determine estimated gestational age)

Table 2. Expanded endpoints

Birth outcomes	Maternal outcomes	Neonatal/infant outcomes
Stillbirth*	Mortality (during pregnancy, labour/delivery, and through 42 days postpartum)	Neonatal death (within 28 days of birth)
Preterm birth <37 weeks* (and whether spontaneous vs indicated)	Pregnancy and labour/delivery complications	Infant mortality (first year)
Very preterm birth <32 weeks* (and whether spontaneous vs indicated)	Eclampsia/pre-eclampsia	Growth (first year)
Birthweight	Weight gain in pregnancy (low/normal/high, per Institute of Medicine; and absolute weight gain by estimated gestational age)
Small for gestational age (SGA) (<10th percentile)*	Caesarean section (emergency vs. elective)
Congenital anomaly, with neonatal surface exam
Miscarriage (any miscarriage <28 weeks; early miscarriage <20 weeks)*

Table 3. Comprehensive endpoints

Birth outcomes	Maternal outcomes	Neonatal/infant outcomes
Stillbirth	Mortality (during pregnancy, labour/delivery, and through 1 year postpartum)	Neonatal death (within 28 days of birth)
Preterm birth <37 weeks* (and whether spontaneous vs indicated)	Pregnancy and labour/delivery complications	Infant mortality (first year)
Very preterm birth <32 weeks* (and whether spontaneous vs indicated)	Eclampsia/pre-eclampsia; also, any hypertension (and blood pressure measurements)	Growth (first year)
Birthweight	Weight gain in pregnancy (low/normal/high, per Institute of Medicine; and absolute weight gain by estimated gestational age)	Congenital anomalies (through 6 months of age)
Small for gestational age (SGA) (<10th percentile)*	Caesarean section (emergency vs. elective)	Hospitalization (first year)
Congenital anomaly, with neonatal surface exam and fetal anatomic ultrasound	Gestational diabetes	Additional lab testing to assess for toxicity (type of testing to depend on drug)
Miscarriage (any miscarriage <20 weeks; any miscarriage <28 weeks)*	Liver, neuropsychiatric, renal, bone toxicity (depending on drug)	Neurodevelopment

Table 4. Key predictor data

Core	Expanded (in addition to core)	Comprehensive (in addition to core/expanded)
Date of delivery	Sociodemographic factors	Smoking, alcohol, substances
Maternal age at delivery	Other medications	Blood pressure measurements (also an outcome measure)
Location of delivery (village/town/city)	Obstetric history	Gestational diabetes screening (also an outcome measure)
Infant sex	Singleton vs multiple birth	Haemoglobin/anaemia (also an outcome measure)
Delivery in a facility vs. out of facility (and which facility)	Chronic and acute medical conditions	Supplements (iron, folate, multivitamins, etc.)
Exposure to drug of interest during pregnancy (yes/no)	Infection, including HIV and STIs (for HIV: CD4 count, viral load, antiretroviral regimen); TORCH infections
Gestational age of first exposure to drug of interest (or at least whether drug exposure started pre-conception, or in the 1st, 2nd, or 3r trimesters)	Infant feeding method (and if breastfed, age at weaning)
Pre-pregnancy BMI (or weight if BMI not available); weight gain during pregnancy, or weight in each trimester (note: weight is both a predictor & outcome)

(Glossary: BMI: body mass index; STI: sexually transmitted infection; TORCH: toxoplasmosis, others (syphilis, hepatitis B), rubella, cytomegalovirus (CMV) and herpes simplex virus.)

Basic endpoint definitions (for additional detail, please refer to WHO harmonized definitions and data elements)

Stillbirth

Born without sign of life at >28 weeks estimated gestational age
If estimated gestational age not available: born without sign of life, and >1000g birthweight and/or >35cm body length

Miscarriage

Early miscarriage: born without sign of life at <20 weeks estimated gestational age
Any miscarriage: born without sign of life at <28 weeks

Preterm birth

Obtain fetal ultrasound/biometry for dating whenever possible, ideally in the 1^st trimester, at 8 weeks (or in 2^nd trimester if 1^st trimester ultrasound not done); also record first day of last menstrual period

Preterm: live birth at <37 weeks estimated gestational age
Very preterm: live birth at <32 weeks estimated gestational age (important to try to obtain estimated gestational age at birth whenever possible, so that can use SGA instead of birthweight):

Birthweight

Low birthweight: live birth with birthweight <2,500 g

Small for gestational age (SGA)

Preferable to and more informative than birthweight.

SGA: live birth with birthweight below the 10^th percentile for babies of the same gestational age
Very SGA: live birth with birthweight below the 3^rd percentile for babies of the same gestational age
Use quality relevant local population norms if available; if not, use INTERGROWTH-21st

Congenital anomalies

Include anomalies in both liveborn and stillborn babies
Collect as much detail as possible on all apparent anomalies, to optimize classification
Core: anomalies reported in routinely collected data (this will often only be for anomalies diagnosed shortly after birth in many settings)
Expanded: add stepwise neonatal surface examination by trained staff, ideally with photos of anomalies reviewed by expert blinded to exposures, to inform anomaly diagnosis (generally also for anomalies diagnosed shortly after birth)
Comprehensive: perform stepwise neonatal surface examination and add fetal anatomic ultrasound for anomaly diagnosis; include anomalies diagnosed through 6 months of age
Focus analyses on major structural abnormalities of prenatal origin that affect health, survival, physical or cognitive functioning of the individual (as per WHO definition).
Specify in advance which anomalies will be considered major vs. minor; and indicate whether a major anomaly that is not evaluated in all infants but happens to be diagnosed (e.g. hip dysplasia, undescended testes, serious heart defect) should be included as an anomaly, in analyses.

Suggest: exclude the following, from primary analyses of anomalies:

Minor anomalies, such as birth marks, positional deformities, postaxial polydactyly type B, umbilical hernia
Functional abnormalities
Findings in a newborn screen
Physiologic findings
Findings consistent with chromosomal or genetic abnormalities
Findings only detected on prenatal ultrasound and not detectable on exam at birth)

Maternal mortality

Core: during pregnancy, intrapartum, and prior to discharge from facility at which delivered
Expanded: through 42 days postpartum
Comprehensive: through 1 year postpartum
Record actual date of death (and estimated gestational age at time of death, if death occurred antepartum; or date of delivery if death occurred postpartum)

Neonatal and infant mortality

Core: death occurring in facility, prior to discharge from facility at which delivered
Expanded: within 28 days of delivery (i.e., neonatal death)
Comprehensive: within 1 year of life (i.e., death within infancy)
Record actual date of death (and date of birth)

Other useful resources

INTERGROWTH21 charts - International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) tools and charts

Global birth defects app for infant outcome assessments - Global Birth Defects Description and Coding (GBDDC) App

ICHOM patient-centered outcome measures - ICHOM Set of Patient-Centered Outcome Measures for Pregnancy and Childbirth

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) - Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation

WHO Birth Defects Training App - Central registry for epidemiological surveillance of drug safety in pregnancy

sSCAN Birth Outcomes Surveillance - Sub-Saharan Congenital Anomalies Network (sSCAN) Birth Outcomes Surveillance Resources - links to papers, resources, and birth defect surveillance app.

DAIDS grading table - Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, July 2017

DAIDS Female Genital Grading Table for Use in Microbicide Studies - Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events - Addendum 1, Female Genital Grading Table for Use in Microbicide Studies. November 2007

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