Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study

Abstract

Summary Background A study of the cause of the epidemic microcephaly in Brazil, including congenital Zika virus infection and other potential causes. Methods Prospective case-control study in Recife/Brazil. Cases: neonates with microcephaly born in public maternities. Controls (without microcephaly) matched by expected date of delivery and area of residence. Laboratory tests: Serum of cases/ controls and cerebrospinal fluid of cases (qRT-PCR and anti-Zika-IgM); tissues of stillbirth cases qRT-PCR). Maternal serum (PRNT for Zika and dengue). The association between microcephaly and ZIKV infection quantified using exact conditional logistic regression. Findings We included 91 cases and 173 controls. Congenital ZIKV infection was confirmed in 32/91 cases compared to 0/173 controls. 83%(68/83) of cases were small for gestational age; 5%(8/173) of controls. The overall matched odds ratio (mOR) was 87 (95%CI:15·6-∞), and 73·1(95%CI:13·0-∞) when adjusted. No controls had laboratory confirmed Zika. Neither vaccinations during pregnancy nor larvicide use was associated with microcephaly. mORs in subgroups were: severe microcephay 52·4 (95%CI:9·1-∞); less severe 33·7 (95%CI:5·6-∞); abnormal brain image 32·2 (95%CI:5·3-∞), and normal brain image 29·3 (95%CI:4·8-∞). About half cases (49/91) had either laboratory confirmation of Zika or typical brain imaging abnormalities but only 15% (12/79) had both. Interpretation Congenital Zika infection caused the microcephaly epidemic in Brazil. Neither larvicides nor vaccinations during pregnancy increased the risk of microcephaly. Neither negative Zika laboratory results nor normal brain image alone is sufficient to discard Zika as a cause of individual cases of microcephaly. Source of funding The study was funded by the Brazilian Ministry of Health and the Pan American Health Organization and AREAS. Some of the investigators received partial support from the National Advisory Board of Scientific and Technological Development (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq]; scholarship 306708/2014-0 to CMTM, 308818/2013-0 to RAAX, 308590/2013-9 to DBMF, 308491/2013-0 to MFPMA, 304174/2014-9 to CB, and 306222/2013-2 to WVS). LCR is partially funded by the European Union’s Horizon 2020 research and innovation program under Zika-PLAN (grant agreement No. 734584).