It has become clear that in some South and Central American countries, particularly Brazil, Zika infection of pregnant women is associated with a range of birth defects, including microcephaly, cerebral calcifications, cerebellar atrophy, visual defects, arthrogryposis, limb reduction defects, and many other problems, as well as later-onset problems in infants who did not have obvious defects detected in utero or at birth. These later issues include ocular damage, delayed development, seizures, feeding problems, and persistent crying. The scope and incidence of these problems are being intensively studied, and many questions remain unanswered.
In early 2016 in northeastern Brazil, a temporal–geographic association between epidemic Zika and epidemic microcephaly caused widespread alarm and declaration of a “public health emergency of international concern” by the World Health Organization (WHO). Many of these babies with microcephaly/other birth defects as well as aborted fetuses have been found to have Zika infection or Zika RNA sequences—sometimes in neural tissue—indicating active infection. In the northeastern Brazilian state of Bahia, the incidence of microcephaly in fetuses of pregnant women infected during the first trimester is reported to be between 1% and 13%. Other countries in the Americas and elsewhere have reported proven or suspected cases of microcephaly/other fetal malformations that are potentially associated with Zika infection of pregnant women; however, to date, the apparent incidence rates are considerably lower than those seen in northeastern Brazil. Curiously, other areas of Brazil that have experienced Zika epidemics have reported far fewer cases of birth defects than has northeastern Brazil.
Similarly, most other countries of the region with significant Zika epidemics have reported, as of September 2016, far lower incidences of microcephaly/birth defects or lesser elevation of birth defect incidence rates. That only one South American country (and predominantly only one region within that country) has thus far had a far higher reported incidence of Zika-associated birth defects than all others remains unexplained. Possibilities that have been proposed include differences in the timing of the epidemics (portending later rises in birth defect incidences in countries with low incidences to date, as infected pregnant women begin to come to term), different incidence rates of infection in pregnant women, an undetected agent other than Zika serving as the true primary causal agent (considered unlikely by most experts), or the involvement of one or more unidentified cofactors in Zika-associated birth defects. Studies of Zika pathogenesis and natural history following fetal infection are in progress, as are studies in an experimental rhesus macaque model.
In classical conceptualizations of teratogenicity, the risk to the fetus is thought to be greatest during the time of maximal organ development—i.e., at ~6–14 weeks for the fetal brain—and before development of the fetal immune system, consistent with teratogenicity data for other viruses that identify the time of maximal risk as being within the first trimester. However, the pathogenesis and natural history of Zika microcephaly have not yet been established. Much lower reported frequencies of damage to specific fetal organs other than the brain and eye raise the possibility that Zika could be damaging the fetus not through teratogenic disruption of organ development, but through aggressive viral encephalitis not controlled by either the fetal immune system (which might recognize the virus as “self” because of first-trimester infection) or by maternal antiviral antibody that crosses the placenta. Accumulating in vitro and animal studies demonstrating the extraordinary neurotropism of Zika virus favor the direct neurotoxic effect as the cause of microcephaly and of the brain damage occurring later in the developmental process of the fetal brain, which is referred to as the “fetal brain disruption syndrome.”
Available data have not yet quantified the risks of Zika virus in pregnancy, although two relatively robust studies have estimated incidences of severe birth defects of all types in Zika-infected pregnant women at ~1–29%. As would be expected from experiences with other viral teratogens, especially rubella, studies are beginning to suggest, as of mid-2016, that the most severe birth defects, including profound microcephaly, tend to result from first-trimester or early second-trimester Zika infections.
Some studies have claimed that symptomatic disease (e.g., illness with rash) in pregnant women is more likely to lead to fetal infection than asymptomatic infection; however, many of those data have been generated by retrospective methods, and babies with apparent congenital Zika infection have been delivered by women who did not have recognized Zika infection. Clinical data and experimental primate data suggest that pregnant Zika-infected women may be viremic for longer periods than nonpregnant infected women or infected men; however, it is not known whether this difference is due to altered immunity in pregnancy or, as seems more likely, persistent infection of the fetus.
Neurologic complications associated with Zika epidemics continue to be reported at relatively low frequency, estimated at ~1 per 4000 Zika infections for Guillain-Barré syndrome. Other possibly immune-mediated complications have been reported as well, including rare cases of meningoencephalitis and acute myelitis, although causality has not yet been established. In addition to deaths from birth defects and neurologic complications, rare Zika deaths have been reported almost invariably in elderly individuals with unrelated underlying conditions. In two such cases, thrombocytopenia was documented.