Table 1

Participant-level variables of interest

Exposure	Maternal ZIKV infection (diagnosis: confirmed, probable, unlikely; primary, secondary, naïve; viral load)
Exposure	Fetal or placental ZIKV infection (diagnosis: confirmed, probable, unlikely; primary, secondary, naïve; viral load)*
Primary outcomes	Miscarriage (<20 weeks gestation)
	Fetal loss (≥20 weeks gestation)
	Microcephaly (diagnosis: severe microcephaly, microcephaly, normocephaly, macrocephaly; Z-score)
	CZS (diagnosis: confirmed, probable, unlikely)
Secondary fetal outcomes†	Induced abortion with microcephaly (diagnosis: confirmed, probable, unlikely)
	Early fetal death (20–27 weeks gestation)
	Late fetal death (≥28 weeks gestation)
	Late fetal death (≥28 weeks gestation) with microcephaly
	Placental insufficiency (diagnosis: confirmed, probable, unlikely)‡
	Intrauterine growth restriction
Secondary infant outcomes†	Postnatal microcephaly (diagnosis: severe microcephaly, microcephaly, normocephaly, macrocephaly; Z-score)
	Gestational age at birth
	Birth weight (diagnosis: normal birth weight; low birth weight; very low birth weight; extremely low birth weight; Z-score)
	Craniofacial disproportion
	Neuroimaging abnormalities (intracranial calcification, lissencephaly, hydranencephaly, porencephaly, ventriculomegaly, posterior fossa abnormalities, cerebellar hypoplasia, corpus callosal and vermian dysgenesis; focal cortical dysplasia)
	Postnatal intraventricular haemorrhage
	Motor abnormalities (hypotonia, hypertonia, hyperreflexia, spasticity, clonus, extrapyramidal symptoms)§
	Seizures, epilepsy§
	Ocular abnormalities (blindness, other)§
	Congenital deafness or hearing loss§
	Congenital contractures (arthrogryposis, unilateral or bilateral clubfoot)
	Other non-neurological congenital abnormalities
Secondary outcomes detected after the infant period¶	Cortical auditory processing
	Neurodevelopment (expressive and receptive language, fine and gross motor skills, attention and executive function, memory and learning, socioemotional development, overall neurodevelopmental score)
	Vision (Cardiff test)
Posited confounders	Demographic factors (age, education, marital status, racial/ethnic group; BMI)
	Socioeconomic factors
	Maternal smoking, illicit drug and alcohol use
	Maternal prescription drug use, vaccination
	Maternal experience of violence during pregnancy; infant or child exposure to intimate partner violence127
	Workplace or environmental exposures to teratogenic substances (eg, maternal exposure to lead, mercury)
Potential effect measure modifiers	Genetic anomalies, metabolic disorders, perinatal brain injury
	Gestational age, term at birth
	Timing of infection during pregnancy
	Clinical/subclinical illness
	Viral genotype and load
	Concurrent or prior flavivirus or alphavirus infection
	Maternal history of YF or JE vaccination
	Maternal immunosuppressive conditions, disorders, comorbidities (eg, chronic hypertension, diabetes) or pregnancy-related conditions (eg, pre-eclampsia, gestational diabetes)
	Intrauterine exposure to STORCH pathogens
	Maternal malnutrition
	Presence and severity of maternal and infant clinical symptoms

*Fetal ZIKV infection will be considered as both an exposure and an outcome; definition of fetal infection will be based on clinical and radiological criteria defined by an expert panel.
†Both with and without microcephaly.
‡As estimated by antenatal consequences of placental insufficiency, including fetal growth restriction, oligohydramnios, non-reassuring fetal heart rate tracing or small for gestational age at birth as markers of placental insufficiency.
§May also be detected after the infant period.
¶As measured by the Bayley Scale;128 Ages and Stages;129 INTERGROWTH-21st Neurodevelopmental Assessment.49
BMI, body mass index; CZS, congenital Zika syndrome; JE, Japanese encephalitis; STORCH, syphilis, toxoplasmosis, rubella, cytomegalovirus and herpes; YF, yellow fever virus; ZIKV, Zika virus