Clinical Review
Zika virus: Counseling considerations for this emerging perinatal threat
Zika virus infection, although typically mild and often asymptomatic, can have serious consequences in pregnancy. As the pandemic rapidly spreads...
Zika virus has been shown to be a direct cause of microcephaly
To make the determination that Zika virus (ZV) causes microcephaly, Rasmussen and colleagues1 very recently evaluated Shepard’s 7 criteria,2 published in 1994, for establishing a cause between a microorganism and a specific clinical condition. These 7 criteria are:
- There must be a proven exposure at one or more critical times during prenatal development.
Rasmussen and colleagues1 pointed to case reports, case series, and epidemiologic studies showing a clear association between ZV exposure and microcephaly. Although exposure at any time during pregnancy may cause congenital infection, exposure in the late first and early second trimesters seems to pose the most risk for severe central nervous system (CNS) injury. - There must be consistent findings in 2 or more high-quality epidemiologic studies.
The studies must control for important confounding variables and include an appropriate number of patients to clearly identify an association between a given exposure and specific fetal anomalies. Rasmussen and colleagues1 cited 2 important epidemiologic studies. The first, a prospective cohort investigation of women in Brazil, found that 29% of those with ZV infection had abnormalities on prenatal ultrasound.3
In the second investigation, a retrospective study of 8 infants in French Polynesia, the mathematical modeling performed by the authors4 suggested microcephaly occurred in 1% of infants born to women with first-trimester ZV infection. Using a different mathematical model, Johansson and colleagues5 found that the risk of fetal microcephaly associated with first-trimester infection may range from as low as 1% to as high as 13%.
Although these studies are helpful in quantifying the risk of congenital infection, they only partially satisfy Shepard’s second criterion. - The suspected microorganism must produce a specific defect or clearly delineated syndrome.
Rasmussen and colleagues1 argued that this criterion has been fulfilled. Zika virus infection causes a distinct phenotype that includes microcephaly, multiple other CNS anomalies, redundant scalp skin, ocular abnormalities, joint contractures (arthrogryposis), and clubfoot.6,7 - The observed birth defect must be associated with a rare environmental exposure.
This criterion also has been met, Rasmussen and colleagues1 reported. They noted that congenital microcephaly is rare in the United States (only about 6 cases in 10,000 liveborn infants) but that the number of cases in Brazil and French Polynesia is much in excess of what would be predicted in the absence of the ZV epidemic. - Teratogenicity should be demonstrated in laboratory animals.
Shepard indicated that this criterion is important but not essential to prove causation. As there is yet no animal model for ZV infection, this criterion has not been fulfilled. - The association between the exposure and the observed anomaly or spectrum of anomalies should be biologically plausible.
Rasmussen and colleagues1 demonstrated that the findings linked to maternal ZV infection are similar to those described for at least 2 other viral pathogens, rubella virus and cytomegalovirus. Animal models also have clearly shown that the ZV is neurotropic. Moreover, ZV has been clearly identified in the brains of infants with microcephaly.8 - Shepard’s seventh criterion relates to a medication or chemical exposure and is not relevant to a microorganism.
References
- Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika virus and birth defects—reviewing the evidence for causality. N Engl J Med. 2016;374(20):1981–1987.
- Shepard TH. “Proof” of human teratogenicity. Teratology. 1994;50(2):97–98.
- Brasil P, Pereira JP Jr, Raja Gabaglia C, et al. Zika virus infection in pregnant women in Rio de Janeiro—preliminary report [published online ahead of print March 4, 2016]. N Engl J Med. doi:10.1056/NEJMoa1602412.
- Cauchemez S, Besnard M, Bompard P, et al. Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study. Lancet. 2016;387(10033):2125–2132.
- Johansson MA, Mier-Y-Teran-Romero L, Reefhuis J, Gilboa SM, Hills SL. Zika and the risk of microcephaly [published online ahead of print May 25, 2016; updated June 9, 2016]. N Engl J Med. 2016;375:1–4. doi:10.1056/NEJMp1605367.
- Meaney-Delman D, Rasmussen SA, Staples JE, et al. Zika virus and pregnancy: what obstetric health care providers need to know. Obstet Gynecol. 2016;127(4):642–648.
- Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med. 2016;374(16):1552–1563.
- Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374(10):951–958.
