Zika virus and microcephaly- the facts

The Timeline:

An outbreak of Zika virus was reported from northeast Brazil in early 2015- an area where dengue virus was already circulating.

By September 2015, reports of an increase in the occurrence of microcephaly in the zika virus affected areas were received.

Subsequently, the Brazil Ministry of Health (MoH) developed

a case definition for Zika virus–related microcephaly (head circumference ≥2 standard deviations [SD] below the mean for sex and gestational age at birth);

and established

a task force (to investigate the possible association of microcephaly with Zika virus infection during pregnancy)
a registry (for incident microcephaly cases (head circumference ≥2 standard deviations [SD] below the mean for sex and gestational age at birth) and pregnancy outcomes among women suspected to have had Zika virus infection during pregnancy)

In October the MoH confirmed an increase in incidence of microcephaly (compared to previous rates).

On November 17, 2015, the MoH reported the increase in microcephaly cases, and possible association of microcephaly with Zika virus infection during pregnancy on its website; and the Pan American Health Organization (PAHO) published an alert regarding the increase in occurrence of microcephaly in Brazil.

In December, PAHO reported the identification of Zika virus RNA

by reverse transcription-polymerase chain reaction (RT-PCR) in amniotic fluid samples from two pregnant women whose fetuses were found to have microcephaly by prenatal ultrasound
from multiple body tissues, including the brain, of an infant with microcephaly who died in the immediate neonatal period

These events prompted new alerts from the MoH, the European Centre for Disease Prevention and Control, and CDC concerning the possible association of microcephaly with the recent outbreak of Zika virus infection.

A comprehensive protocol for notification and investigation of all infants with microcephaly and all women with suspected Zika virus infection during pregnancy was developed by the MoH and implemented nationwide. The protocol included history and physical examination.

Infection with Zika virus is difficult to confirm retrospectively because serological immunological tests might cross-react with other flaviviruses, especially dengue virus. Therefore a mother’s report of a rash illness during pregnancy was used as a proxy indicator of potential Zika virus infection.

CDC recently tested samples from two pregnancies that ended in miscarriage and from two infants with microcephaly who died shortly after birth. All four cases were from Brazil and were positive for Zika virus infection, indicating that the infants had become infected during pregnancy. Zika virus was present in the brain of the full term infants, and genetic sequence analyses show that the virus in all four cases was the same as the Zika virus strain currently circulating in Brazil. All four mothers reported having experienced a febrile rash illness during their pregnancies.

Limitations/ Precautions:

The routine reporting of microcephaly in Brazil was less than expected values, indicating under-reporting prior to the zika virus outbreak. After the implementation of the MoH’s special notification protocol during the second half of 2015, the occurrence of microcephaly sky-rocketed- possibly due to greater reporting.
Prior to implementation of the special notification protocol, although congenital malformations were reported, infant head circumference was not measured routinely. After the implementation of the special notification protocol, physicians began measuring head circumference routinely- possibly detecting mild cases of microcephaly that would have been missed earlier.
Since Zika virus infection was not laboratory-confirmed in (all but a very small proportion of) infants or their mothers, the history of a nonspecific rash illness during pregnancy is subject to recall bias and might have resulted in misclassification of potential Zika virus exposure.

Requirements for establishing a causal relationship between zika virus and occurrence of microcephaly:

Strength: Strong associations (20 times increased risk of a condition among those exposed as compared to the unexposed, for instance) are more likely to be causal. Weaker associations are likely to be blamed on chance and possible confounders.

Status: Unknown. Research based evidence is lacking- we cannot state the magnitude of association between zika virus and microcephaly at present.

Consistency: The same findings should be reported by various investigators from a variety of settings.

Status: Apart from Brazil, a few other countries have also reported an increase in congenital malformations. However, zika virus has been around for several decades, and was not associated with such conditions till recently. It is not possible to comment on consistency at present.

Temporality: The zika virus outbreak should have preceded the increase in occurrence of microcephaly.

Status: Satisfied

Specificity: This could be specificity of exposure (nature/ timing, etc.) associated with occurrence of a condition.

Status: Unknown. We do not know if zika virus exposure during a specific time of pregnancy alone is associated with microcephaly/ congenital malformations, for instance.

Biological gradient: Is a dose-response curve demonstrable(as exposure increases, so does occurrence of condition)?

Status: Unknown.

Plausibility: Is it possible to explain how the exposure would have lead to occurrence of condition? This depends upon the knowledge available at the time. As this is dynamic, what seems implausible today may be plausible tomorrow.

Status: Unknown. We do not fully understand the effect(s) zika virus has on the human body.

Coherence: Do the temporal patterns of exposure and the known biological effects of the exposure fit the observed disease patterns?

Status: Unknown. We do not know enough about the exposure and/or its biological effects at present.

Experiment: Do preventive actions taken on the basis of a demonstrated cause-and-effect relationship alter the frequency of the outcome?

Status: Unknown. There are a few known confounders- preventive actions will likely influence these as well, making it difficult to clearly establish any such relationship.

Note: Recent reports of an association between a pesticide and the increased occurrence of microcephaly are also under investigation.