niman

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  1. Eur J Hum Genet. 2009 Feb; 17(2): 147–149. Published online 2008 Oct 22. doi: 10.1038/ejhg.2008.198 PMCID: PMC2986051 On Jim Watson's APOE status: genetic information is hard to hide Dale R Nyholt,1,* Chang-En Yu,2 and Peter M Visscher1 Author information ► Copyright and License information ► This article has been cited by other articles in PMC. The recent publication and release to public databases of Dr James Watson's sequenced genome,1 with the exception of all gene information about apolipoprotein E (ApoE), provides a pertinent example of the challenges concerning privacy and the complexities of informed consent in the era of personalized genomics.2 Dr Watson requested that his ApoE gene (APOE) information be redacted, citing concerns about the association that has been shown with late onset Alzheimer's disease (LOAD), which is currently incurable and claimed one of his grandmothers.3 In this letter, without any ‘analysis' of Dr Watson's genome, and thus respecting Dr Watson's wishes for APOE risk status anonymity, we highlight the challenges concerning the privacy and the complexities of informed consent by pointing out that the deletion of the APOE gene information only may not prevent accurate prediction of Dr Watson's risk for LOAD conveyed by APOE risk alleles. Specifically, linkage disequilibrium (LD) between one or multiple polymorphisms and APOE can be used to predict APOE status using advanced computational tools. Therefore, simply blanking out genotypes at known risk factors is generally not sufficient if the aim is to hide genetic information at these loci. The major APOE risk for LOAD is generally assumed to come from the ɛ2/ɛ3/ɛ4 haplotype system, with the ɛ4 allele increasing risk for the disorder and the ɛ2 allele being protective.4 The ɛ2/ɛ3/ɛ4 haplotype system is defined by two nonsynonymous single nucleotide polymorphisms (SNPs) in APOE exon 4. One is a C/T SNP (rs429358) that encodes either arginine (C) or cysteine (T) in the ApoE at amino acid 112. The second site defining this haplotype system is a C/T SNP (rs7412), which again encodes arginine (C) or cysteine (T) at ApoE amino acid 158. The allelic compositions of the commonly investigated rs429358-rs7412 haplotypes are T-T for ɛ2, T-C for ɛ3, and C-C for ɛ4. The effects of these coding variants on ApoE function are well defined.5 A recent meta-analysis of LOAD risk in Caucasians (clinic/autopsy cohorts) indicated odds ratios (OR) of 15.6 (95% CI, 10.9–22.5) and 4.3 (95% CI, 3.3–5.5) for APOE ɛ4 homozygotes and ɛ4/ɛ3heterozygotes respectively, compared to ɛ3 homozygotes.6 The meta-analytic odds ratios in population-based Caucasian samples were 11.8 (95% CI, 7.0–19.8) and 2.8 (95% CI, 2.3–3.5), respectively.6 In a large Rotterdam (Netherlands), population-based prospective study of people aged 55 years or above, it was estimated that 17% of the overall risk of AD could be attributed to the ɛ4 allele, with 3% (95% CI, 0–6%) of cases attributed to the ɛ4/ɛ4 genotype, and 14% (95% CI, 7–21%) to the ɛ4/ɛ3 genotype.7 A recent investigation of LD for 50 SNPs in and surrounding APOE in 550 Caucasians identified multiple SNPs in the TOMM40 gene ∼15 kb upstream of APOE, and at least one SNP in the other surrounding genes LU, PVRL2, APOC1, APOC4 and CLPTM1 were associated with LOAD risk.8 In particular, the C allele of SNP rs157581 in TOMM40 is in strong LD (r2>0.6) with the C allele of rs429358 in APOE, which defines the ɛ4 allele. For an additive (allelic) logit model, the OR for the presence of ɛ4 versus the status of LOAD was estimated to be 4.1, whereas the OR for LOAD status using the alleles of rs157581 was 2.9.8Furthermore, using data sets such as those of Yu et al8 and SNPs identified in the surrounding regions of APOE in Dr Watson's sequence, haplotype phasing software could be utilized to easily and accurately predict Dr Watson's APOE risk haplotype status. In addition, even if genotypes for non-APOE SNPs conveying LOAD risk are not listed in Dr Watson's sequence (ie, because of low sequence coverage), as in the case of TOMM40 SNP rs157581, it would be straightforward to predict Dr Watson's APOE risk status by exclusively using publicly available data, such as HapMap data. Specifically, although the LOAD high-risk APOE SNPs rs429358 and rs7412 and TOMM40 SNP rs157581 are not in the HapMap, a recent genome-wide association screen using 502 627 SNPs performed in 1086 histopathologically verified LOAD cases (n=664) and controls (n=442), identified HapMap SNP rs4420638, located in the APOC1 gene 14 kb downstream of the APOE ɛ4 allele, which has a powerful association with LOAD.9 Indeed, the association between LOAD and the G allele of rs4420638 (P=1 × 10−39) is similar to the association with the APOE ɛ4 allele (rs429358 C allele) itself (P=1 × 10−44), with additive allelic ORs of approximately 4 and 5, respectively.9, 10 Coon et al9 report strong LD between rs4420638 and rs429358 at D′=0.86, which implies an r2 of approximately 0.60 based on Caucasian allele frequency estimates for these SNPs listed in dbSNP. We note that Dr Watson received genetic counseling and after being made aware of the privacy risks associated with public data broadcast, Dr Watson decided to share his personal genome by releasing it into a publicly accessible scientific database (for full details concerning Dr Watson and Protection of human subjects, Returning research results to research participants, and Data release and data flow, see Box 1 of Wheeler et al1). Nevertheless, during the preparation of this Letter, we contacted Dr Watson and colleagues in December 2007 and February 2008 informing them of the possibility of inferring his risk for LOAD conveyed by APOE risk alleles using surrounding SNP data. As a consequence, the online James Watson Genome Browser (JWGB) has nominally removed all data from the 2-Mb region surrounding APOE. To demonstrate our point that genetic information is hard to hide, without contravening Dr Watson's wishes for APOE risk status anonymity (see Box 1 of Wheeler et al1), we utilized SNP genotypes identified in Dr J Craig Venter's genome sequence.11 Furthermore, Dr Venter's sequence data reports that he is heterozygote for both the LOAD high-risk APOE SNP rs429358 (T/C) and APOC1 SNP rs4420638 (A/G). Briefly, genotype imputation was performed using the MACH (version 1.0.16) computer program,12 HapMap (CEU)-phased haplotype data (encompassing 144 SNPs) and Dr Venter's genotypes listed for the 200-kb region surrounding rs4420638 (encompassing all 144 HapMap SNPs). Following the two-step approach outlined in the MACH online tutorial and after excluding Dr Venter's genotype data for rs4420638 and all APOE SNPs, we were able to correctly impute Dr Venter's rs4420638 genotype as A/G. The posterior probabilities for Dr Venter's rs4420638 genotype being A/A, A/G or G/G were estimated to be 0.008, 0.992 and 0.000, respectively. The high accuracy of Dr Venter's imputed rs4420638 genotype exemplifies the utility of imputing APOE genetic risk for LOAD. Finally, although the deletion of 2 Mb is likely excessive for the surrounding APOE region (based on reported LD), as more detailed characterization of the human genome comes to light, it will become even more necessary to redact substantial regions surrounding identified genetic risk variants to avoid the indirect, though accurate, estimation of genetic risk such as those we detail above. For example, in a recent study, using gene expression profiling of Epstein–Barr virus-transformed lymphoblastoid cell lines of all 270 individuals genotyped in the HapMap Consortium, Stranger et al13 reported many instances of the most significant SNP associated with gene expression being located often 100 s of kb and up to 1 Mb outside of the gene transcript, with additional, less significant SNPs, although still useful in estimating risk, being located even further from the gene. Moreover, the potential for indirect estimation of risk will further increase as additional and more detailed genome-wide association studies are performed (which identify new risk loci) and individual human genomes are sequenced. In summary, hiding genetic information in an otherwise fully disclosed genome sequence is not straightforward because of the availability of genomic data in the public domain that can be used to predict the missing data. We believe the potential for such indirect estimation of genetic risk has considerable relevance to concerns about privacy, confidentiality, discriminatory and defamatory use of genetic data, and the complexities of informed consent for both research participants and their close genetic relatives in the era of personalized genomics. Acknowledgments This study was supported by Australian NHMRC Grants 389892, 339462 and 442915 and Australian Research Council Grant DP0770096. Footnotes Conflict of interest None declared. Web Resources The URL for data presented here are as follows: James Watson Genome Browser (JWGB), http://jimwatsonsequence.cshl.edu/cgi-perl/gbrowse/jwsequence/ James Watson Genome Browser (JWGB); local copy installation download, ftp://jimwatsonsequence.cshl.edu/jimwatsonsequence/gbrowse/ Dr J Craig Venter's genome sequence, http://huref.jcvi.org/ MACH (version 1.0.16) computer program, http://www.sph.umich.edu/csg/abecasis/MACH HapMap (CEU) phased haplotype data (encompassing 144 SNPs), http://www.hapmap.org/cgi-perl/gbrowse/hapmap_B35/ Dr Venter's genotypes (downloaded on June 19, 2008), ftp://ftp.jcvi.org/pub/data/huref/HuRef.InternalHuRef-NCBI.gff MACH online tutorial, http://www.sph.umich.edu/csg/abecasis/MACH/tour/imputation.html References Wheeler DA, Srinivasan M, Egholm M, et al. The complete genome of an individual by massively parallel DNA sequencing. Nature. 2008;452:872–876. [PubMed] McGuire AL, Caulfield T, Cho MK. Research ethics and the challenge of whole-genome sequencing. Nat Rev Genet. 2008;9:152–156. [PMC free article] [PubMed] Check E. James Watson's genome sequenced – discoverer of the double helix blazes trail for personal genomics Nature News 2008. doi:10.1038/news070528-10 :http://www.nature.com/news/2007/070528/full/news070528-10.html [Cross Ref] Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278:1349–1356. [PubMed] Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging. 2004;25:641–650. [PubMed] Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39:17–23. [PubMed] Slooter AJ, Cruts M, Kalmjin S, et al. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Ann Neurol. 1998;55:964–968. [PubMed] Yu CE, Seltman H, Peskind ER, et al. Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimer's disease: patterns of linkage disequilibrium and disease/marker association. Genomics. 2007;89:655–665. [PMC free article] [PubMed] Coon KD, Myers AJ, Craig DW, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J Clin Psychiatry. 2007;68:613–618. [PubMed] Reiman EM. In this issue: entering the era of high-density genome-wide association studies. J Clin Psychiatry. 2007;68:611–612. [PubMed] Levy S, Sutton G, Ng PC, et al. The diploid genome sequence of an individual human. PLoS Biol. 2007;5:e254. [PMC free article] [PubMed] Li Y, Abecasis GR. Mach 1.0: rapid haplotype reconstruction and missing genotype inference. Am J Hum Genet. 2006;S79:2290. Stranger BE, Nica AC, Forrest MS, et al. Population genomics of human gene expression. Nat Genet. 2007;39:1217–1224. [PMC free article] [PubMed] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986051/ Articles from European Journal of Human Genetics are provided here courtesy of Nature Publishing Group
  2. NY Times has a report on 23andme FDA approved test for late onset Alzheimer's disease and impact on long term care heath insurance. However, the determination of APOE4 status can be determined through additional markers on Chromosome 19.
  3. New Gene Tests Pose a Threat to Insurers By GINA KOLATA MAY 12, 2017 https://www.nytimes.com/2017/05/12/health/new-gene-tests-pose-a-threat-to-insurers.html?smid=tw-nythealth&smtyp=cur&_r=0 Photo Pat Reilly, 77, at home in Ann Arbor, Mich., last week. Ms. Reilly found that she had inherited an ApoE4 gene that increases the risk of developing Alzheimer’s disease, and bought a long-term care policy in response.CreditLaura McDermott for The New York Times Pat Reilly had good reason to worry about Alzheimer’s disease: Her mother had it, and she saw firsthand the havoc it could wreak on a family, much of it financial. So Ms. Reilly, 77, a retired social worker in Ann Arbor, Mich., applied for a long-term care insurance policy. Wary of enrolling people at risk for dementia, the insurance company tested her memory three times before issuing the policy. But Ms. Reilly knew something the insurer did not: She has inherited the ApoE4 gene, which increases the lifetime risk of developing Alzheimer’s. “I decided I’d best get long-term care insurance,” she said. An estimated 5.5 million people in the United States have Alzheimer’s disease, and these patients constitute half of all nursing home residents. Yet very few people in the United States have been tested for the ApoE4 gene. But last month, with the approval of the Food and Drug Administration, the gene testing company 23andMe began offering tests that reveal whether people have the variant, as well as assessing their risks for developing such conditions as Parkinson’s and celiac disease. Other genetics companies are planning to offer similar tests, and soon millions of people will have a better idea what their medical futures might be. Recent research has found that many, like Ms. Reilly, are likely to begin preparing for the worst. But for companies selling long-term care insurance, these tests could be a disaster, sending risky patients in search of policies even as those with fewer risks shy away, damaging an already fragile business. “There is a question about whether the industry is in a death spiral anyway,” said Robert Hunter, director of insurance at the Consumer Federation of America. “This could make it worse.” The tests are simple: All people have to do is send away a saliva sample and pay $199. Their disease risks, if they say they want to know them, will be delivered with a report on ancestry and on how their genes influence such traits as flushing when they drink alcohol or having straight hair. The company will not reveal how many people have received disease-risk data, but it says that in Britain and Canada, where it has offered such testing for several years, about three-quarters of their customers have asked for it. 23andMe has sold its genetic services to more than two million people worldwide since 2007. The issue for now is with long-term care insurance, not employment and not — at least so far — health insurance. Under the Genetic Information Nondiscrimination Act, companies cannot ask employees to take gene tests and cannot use any such results in employment decisions; insurers are not permitted to require gene tests or to use the results in coverage decisions. But legislation proposed in the House would exempt corporate “wellness” programs from some of these requirements. And the American Health Care Act, passed by the House, would permit states to waive some insurance safeguards regarding pre-existing conditions. At the moment, companies selling long-term care insurance — unlike medical insurers — are permitted to ask about health status and take future health into consideration when deciding whom to insure and how much to charge. The 23andMe test results will not appear in people’s medical records, and the company promises not to disclose identifiable findings to third parties. It is up to the customers to reveal them — and the fear for insurers is that many will not. Two-thirds of nursing home residents are on Medicaid, and the remaining private insurers are already struggling. In the early 2000s, more than 100 firms offered long-term care insurance, according to the Treasury Department. By the end of 2015, only 12 firms offered it, and new enrollees fell from 171,000 to 104,000. The insurers charged too little for these policies, experts say; policyholders have turned out to be much sicker than anticipated. To pay for an unanticipated increase in policyholders who develop Alzheimer’s, insurers would have to raise prices, said Don Taylor, a professor of public policy at Duke University who has studied the issue. Increasing numbers of people at low risk might decide the insurance was not worth the rising price. Even many at high risk would eventually find the policies unaffordable. It is the definition of an insurance death spiral. If that happens, said Mark Rothstein, the director of the bioethics institute at the University of Louisville’s medical school, even more people with Alzheimer’s will end up on Medicaid, with the federal government paying for their nursing home care. Someone must pay, he said. The only question is whether it will be taxpayers or policyholders. “How do you want to spread the risk?” Mr. Rothstein asked. For 23andMe, the new tests are simply a way to help people learn about their makeup. “People clearly want information about themselves,” said Anne Wojcicki, the chief executive at 23andMe. “There is a demand.” Yet even if just a minority of 23andMe customers decided to game the current insurance system, “it’s enough to perturb the market,” said Dr. Robert Cook-Deegan, a professor at the school for the future of innovation in society at Arizona State University, who has studied the issue. Research by Dr. Robert C. Green, a geneticist at Harvard University, indicates that this is exactly what is likely to happen. Drawing on data from his clinical trials involving more than 1,000 people, Dr. Green has found that people who learn they have the ApoE4 gene fare just as well if they get the results without counseling. But he also found that those who learned they had the gene variant — Ms. Reilly was one of them — were nearly six times more likely to buy long-term care insurance than those who did not. The ApoE4 gene variant is present in about a quarter of the population. Many thought there was no need to tell the insurer why they suddenly wanted a policy. “All the insurance companies are concerned about this,” said Dr. Green, who has been discussing the problem with industry executives. Major insurers declined to comment. A trade group, American Council of Life Insurers, issued an email statement by Mariana Gomez-Vock, the group’s senior counsel. “Though it is difficult to speculate on the potential impact of the latest 23andMe offering, any situation that has the ability to significantly increase adverse selection could impact the availability and affordability of products over time,” she wrote. “We need to be on the same page with the applicant, where both sides share the same information,” she added. But will that happen? “I don’t see a good outcome here,” Mr. Taylor said. Correction: May 16, 2017 An earlier version of this article misstated the name of the legislation that prevents companies and insurers from using gene tests to make employment or coverage decisions. It is the Genetic Information Nondiscrimination Act, not the Genetic Information Nondiscrimination Privacy Act.
  4. http://www.renseradio.com/listenlive.htm
  5. Interview at 10 PM EDT tonight will include MERS camel sequences & update on South Korea THURSDAY Dr. Henry L. Niman, PhD Flu, Flu, Flu
  6. Tonight at 10 PM - Personal DNA Testing THURSDAY Dr. Henry L. Niman, PhD
  7. FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions SHARE TWEET LINKEDIN PIN IT EMAIL PRINT For Immediate Release April 6, 2017 Release Español The U.S. Food and Drug Administration today allowed marketing of 23andMe Personal Genome Service Genetic Health Risk (GHR) tests for 10 diseases or conditions. These are the first direct-to-consumer (DTC) tests authorized by the FDA that provide information on an individual’s genetic predisposition to certain medical diseases or conditions, which may help to make decisions about lifestyle choices or to inform discussions with a health care professional. “Consumers can now have direct access to certain genetic risk information,” said Jeffrey Shuren, M.D., director of the FDA’s Center for Devices and Radiological Health. “But it is important that people understand that genetic risk is just one piece of the bigger puzzle, it does not mean they will or won’t ultimately develop a disease.” The GHR tests are intended to provide genetic risk information to consumers, but the tests cannot determine a person’s overall risk of developing a disease or condition. In addition to the presence of certain genetic variants, there are many factors that contribute to the development of a health condition, including environmental and lifestyle factors. The 23andMe GHR tests work by isolating DNA from a saliva sample, which is then tested for more than 500,000 genetic variants. The presence or absence of some of these variants is associated with an increased risk for developing any one of the following 10 diseases or conditions: Parkinson’s disease, a nervous system disorder impacting movement; Late-onset Alzheimer’s disease, a progressive brain disorder that destroys memory and thinking skills; Celiac disease, a disorder resulting in the inability to digest gluten; Alpha-1 antitrypsin deficiency, a disorder that raises the risk of lung and liver disease; Early-onset primary dystonia, a movement disorder involving involuntary muscle contractions and other uncontrolled movements; Factor XI deficiency, a blood clotting disorder; Gaucher disease type 1, an organ and tissue disorder; Glucose-6-Phosphate Dehydrogenase deficiency, also known as G6PD, a red blood cell condition; Hereditary hemochromatosis, an iron overload disorder; and Hereditary thrombophilia, a blood clot disorder. The FDA reviewed data for the 23andMe GHR tests through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device. Along with this authorization, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the tests’ accuracy, reliability and clinical relevance. These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for these and similar GHR tests. In addition, the FDA intends to exempt additional 23andMe GHR tests from the FDA’s premarket review, and GHR tests from other makers may be exempt after submitting their first premarket notification. A proposed exemption of this kind would allow other, similar tests to enter the market as quickly as possible and in the least burdensome way, after a one-time FDA review. “The special controls describe the testing that 23andMe conducted to demonstrate the performance of these tests and clarify agency expectations for developers of other GHRs,” said Dr. Shuren. “By establishing special controls and eventually, a premarket review exemption, the FDA can provide a streamlined, flexible approach for tests using similar technologies to enter the market while the agency continues to help ensure that they provide accurate and reproducible results.” Excluded from today’s marketing authorization and any future, related exemption are GHR tests that function as diagnostic tests. Diagnostic tests are often used as the sole basis for major treatment decisions, such as a genetic test for BRCA, for which a positive result may lead to prophylactic (preventative) surgical removal of breasts or ovaries. Authorization of the 23andMe GHR tests was supported by data from peer-reviewed, scientific literature that demonstrated a link between specific genetic variants and each of the 10 health conditions. The published data originated from studies that compared genetic variants present in people with a specific condition to those without that condition. The FDA also reviewed studies, which demonstrated that 23andMe GHR tests correctly and consistently identified variants associated with the 10 indicated conditions or diseases from a saliva sample. The FDA requires the results of all DTC tests used for medical purposes be communicated in a way that consumers can understand and use. A user study showed that the 23andMe GHR tests’ instructions and reports were easy to follow and understand. The study indicated that people using the tests understood more than 90 percent of the information presented in the reports. Risks associated with use of the 23andMe GHR tests include false positive findings, which can occur when a person receives a result indicating incorrectly that he or she has a certain genetic variant, and false negative findings that can occur when a user receives a result indicating incorrectly that he or she does not have a certain genetic variant. Results obtained from the tests should not be used for diagnosis or to inform treatment decisions. Users should consult a health care professional with questions or concerns about results. The FDA granted market authorization of the Personal Genome Service GHR tests to 23andMe, Inc. The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm551185.htm
  8. I have recently begun to look at personal DNA testing. Initial observations are for two of the more popular home tests (23andme and ancestry.com). Both services include raw data on over 500,000 snps, which include many predictive markers for a variety of medical conditions, including cancer. Recently, 10 of the 23andme tests have received FDA approval.
  9. Idaho Payette County in the State of Idaho, on or after December 19, 2014 and before May 19, 2015 as well as on or after April 11, 2017 are ineligible for export.* https://www.fsis.usda.gov/wps/portal/fsis/topics/international-affairs/exporting-products/export-library-requirements-by-country/Nicaragua
  10. Poultry slaughtered on or after March 15, 2017, which originated from or passed through or is slaughtered/processed within the zone shown on the attached map is ineligible. Within the zone, poultry slaughtered and processed before March 15 , 2017 is eligible.* https://www.fsis.usda.gov/wps/portal/fsis/topics/international-affairs/exporting-products/export-library-requirements-by-country/Japan
  11. Idaho Payette County in the State of Idaho, on or after December 19, 2014 and before May 19, 2015 as well as on or after April 13, 2017 are ineligible for export.* https://www.fsis.usda.gov/wps/portal/fsis/topics/international-affairs/exporting-products/export-library-requirements-by-country/Honduras
  12. Idaho - Poultry meat and meat products loaded on board vessel on or before April 10, 2017.* https://www.fsis.usda.gov/wps/portal/fsis/topics/international-affairs/exporting-products/export-library-requirements-by-country/taiwan
  13. References Meaney-Delman D, Hills SL, Williams C, et al. Zika virus infection among U.S. pregnant travelers, August 2015–February 2016. MMWR Morb Mortal Wkly Rep 2016;65:211–4. CrossRef PubMed Simeone RM, Shapiro-Mendoza CK, Meaney-Delman D, et al. ; Zika and Pregnancy Working Group. Possible Zika virus infection among pregnant women—United States and Territories, May 2016. MMWR Morb Mortal Wkly Rep 2016;65:514–9. CrossRef PubMed Honein MA, Dawson AL, Petersen EE, et al. ; US Zika Pregnancy Registry Collaboration. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA 2017;317:59–68. CrossRef PubMed Cragan JD, Mai CT, Petersen EE, et al. Baseline prevalence of birth defects associated with congenital Zika virus infection—Massachusetts, North Carolina, and Atlanta, Georgia, 2013–2014. MMWR Morb Mortal Wkly Rep 2017;66:219–22. CrossRef PubMed Rabe IB, Staples JE, Villanueva J, et al. ; MTS. Interim guidance for interpretation of Zika virus antibody test results. MMWR Morb Mortal Wkly Rep 2016;65:543–6. CrossRef PubMed Council of State and Territorial Epidemiologists. Zika virus disease and Zika virus infection 2016 case definition. CSTE position statement 16-IC-01. Atlanta, GA: Council of State and Territorial Epidemiologists; 2016. https://wwwn.cdc.gov/nndss/conditions/zika/case-definition/2016/06/ Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr 2017;171:288–95. CrossRef PubMed Russell K, Oliver SE, Lewis L, et al. ; Contributors. Update: interim guidance for the evaluation and management of infants with possible congenital Zika virus infection—United States, August 2016. MMWR Morb Mortal Wkly Rep 2016;65:870–8. CrossRef PubMed van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at Birth—Brazil. MMWR Morb Mortal Wkly Rep 2016;65:1343–8. CrossRef PubMed Alarcon A, Martinez-Biarge M, Cabañas F, Quero J, García-Alix A. A prognostic neonatal neuroimaging scale for symptomatic congenital cytomegalovirus infection. Neonatology 2016;110:277–85. CrossRef PubMed Bhatnagar J, Rabeneck DB, Martines RB, et al. Zika virus RNA replication and persistence in brain and placental tissue. Emerg Infect Dis 2017;23:405–14. CrossRef PubMed Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure—United States, July 2016. MMWR Morb Mortal Wkly Rep 2016;65:739–44. CrossRef PubMed
  14. CDCMMWR Vital Signs: Update on Zika Virus–Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure — U.S. Zika Pregnancy Registry, 2016 Early Release / April 4, 2017 / 66 https://www.cdc.gov/mmwr/volumes/66/wr/mm6613e1.htm?s_cid=mm6613e1_w
  15. TABLE 2. Postnatal neuroimaging* and infant Zika virus testing results for 895 liveborn infants in the U.S. Zika Pregnancy Registry — 50 U.S. states and the District of Columbia, 2016 Testing No (%) liveborn infants With birth defects Without birth defects Total Total 45 850 895 Neuroimaging Any neuroimaging reported to USZPR 29 (64) 192 (23) 221 (25) Infant Zika virus testing Positive test result on an infant specimen†,§ 25 (56) 69 (8) 94 (11) Negative infant test results among infants with ≥1 infant specimen reported as tested 17 (38) 474 (56) 491 (55) No infant specimen test results reported to USZPR 3 (7) 307 (36) 310 (35) Abbreviations: IgM= immunoglobulin M; NAT=nucleic acid test; RT-PCR = reverse transcription–polymerase chain reaction; USZPR = U.S. Zika Pregnancy Registry. * Neuroimaging includes any cranial ultrasound, computed tomography, or magnetic resonance imaging test reported to the USZPR. † Positive infant tests included the presence of Zika virus RNA by a positive NAT (e.g., RT-PCR) and/or serological results of IgM positive/equivocal. § Infant specimens include serum, urine, blood, cerebrospinal fluid, cord serum, and cord blood.
  16. TABLE 1. Pregnancy outcomes* for 972 women with completed pregnancies† with laboratory evidence of possible recent Zika virus infection, by maternal symptom status and timing of symptom onset or exposure — U.S. Zika Pregnancy Registry, United States, December 2015–December 2016 Characteristic Brain abnormalities and/or microcephaly (No.) NTDs and early brain malformations, eye abnormalities, or consequences of CNS dysfunction without brain abnormalities or microcephaly (No.) Total with ≥1 birth defect (No.) Completed pregnancies (No.) Proportion affected by Zika virus–associated birth defects, % (95% CI§) Any laboratory evidence of possible recent Zika virus infection¶ Total 43 8 51 972 5 (4–7) Maternal symptom status Symptoms of Zika virus infection reported 18 3 21 348 6 (4–9) No symptoms of Zika virus infection reported 24 4 28 599 5 (3–7) Unknown 1 1 2 25 — Timing of symptoms or exposure** First trimester††,§§ 13 1 14 157 9 (5–14) Multiple trimesters including first 22 6 28 396 7 (5–10) Confirmed evidence of Zika virus infection¶¶ Total 18 6 24 250 10 (7–14) Maternal symptom status Symptoms of Zika virus infection reported 8 3 11 141 8 (4–13) No symptoms of Zika virus infection reported 10 2 12 102 12 (7–19) Unknown 1 0 1 7 — Timing of symptoms or exposure** First trimester††,§§ 8 1 9 60 15 (8–26) Multiple trimesters including first 8 4 12 58 21 (12–33) Abbreviations: CI = confidence interval; CNS = central nervous system; IgM= immunoglobulin M; NAT=nucleic acid test; NTD = neural tube defect; PRNT = plaque reduction neutralization test; RT-PCR = reverse transcription–polymerase chain reaction. * Outcomes for multiple gestation pregnancies are counted once. † Includes live births, spontaneous abortions, terminations, and stillbirths. § 95% CI for a binomial proportion using Wilson score interval. ¶ Includes maternal, placental, or fetal/infant laboratory evidence of possible recent Zika virus infection based on presence of Zika virus RNA by a positive NAT (e.g., RT-PCR) or similar test, serological evidence of a recent Zika virus infection, or serological evidence of a recent unspecified flavivirus infection. ** Estimates were not calculated for exposure in other trimesters because of small numbers. Pregnant women who did not have first trimester exposure might have had exposure in the periconceptional period only (8 weeks before conception or 6 weeks before and 2 weeks after the first day of the last menstrual period), second trimester, third trimester, both the second and third trimester; many women were missing information on trimester of exposure. †† First trimester is defined as last menstrual period +14 days to 13 weeks, 6 days (97 days). §§ First trimester exposure includes women with exposure limited to the first trimester and women with exposure limited to the first trimester and periconceptional period. ¶¶ Includes maternal, placental, or fetal/infant laboratory evidence of confirmed Zika virus infection based on presence of Zika virus RNA by a positive NAT (e.g., RT-PCR) or similar test or serological results of IgM positive/equivocal with Zika PRNT ≥10 and dengue PRNT <10.
  17. Acknowledgments Alabama Zika Response Team, Alabama Department of Public Health; Alaska Division of Public Health; Division of Epidemiology-Disease Surveillance & Investigation, District of Columbia Department of Health; Illinois Department of Public Health Zika Response Team; The Iowa Department of Public Health; Kansas Department of Health and Environment; Kentucky Department for Public Health Zika Pregnancy Workgroup; Michigan Zika Pregnancy Registry Workgroup, Michigan Department of Health and Human Services; Missouri Department of Health and Senior Services; Office of Public Health Informatics and Epidemiology, Nevada Division of Public and Behavioral Health; Oregon Public Health Division Acute and Communicable Disease Program; Center for Acute Infectious Disease Epidemiology, Rhode Island Department of Health; Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services; Texas Department of State Health Services; Wisconsin Division of Public Health. U.S. Zika Pregnancy Registry Collaboration Jennifer Adair, MSW, Maricopa County Department of Public Health, Arizona; Irene Ruberto, PhD, Arizona Department of Health Services; Dirk T. Haselow, MD, PhD, Arkansas Department of Health; Lucille Im, MPH, Arkansas Department of Health; Wendy Jilek, MPH, California Department of Public Health; Monica S. Lehmann, MPH, MSN, California Department of Public Health, Center for Family Health, California Birth Defects Monitoring Program; Richard Olney, MD, California Department of Public Health; Charsey Cole Porse, PhD, California Department of Public Health; Karen C. Ramstrom, DO, California Department of Public Health; Similoluwa Sowunmi, MPH, California Department of Public Health; Natalie S. Marzec, MD, Colorado Department of Public Health and Environment; Karin Davis, Connecticut Department of Public Health; Brenda Esponda-Morrison, Connecticut Department of Public Health; M. Zachariah Fraser, Connecticut Department of Public Health; Colleen Ann O'Connor, MPH, Connecticut Department of Public Health; Wendy Chung, MD, Dallas County Health and Human Services; Folasuyi Richardson, MPH, Dallas County Health and Human Services; Taylor Sexton, MPH, Dallas County Health and Human Services; Meredith E. Stocks, MPH, Dallas County Health and Human Services; Senait Woldai, MPH, Dallas County Health and Human Services; Amanda M. Bundek, Delaware Division of Public Health; Jennifer Zambri, MBA, Delaware Division of Public Health, Office of Infectious Disease Epidemiology; Cynthia Goldberg, Miami, Dade County Health Department, Florida Department of Health; Leah Eisenstein, MPH, Florida Department of Health; Jennifer Jackson, MPH, Orange County Health Department, Florida Department of Health; Russell Kopit, MPH, Palm Beach County Health Department, Florida Department of Health; Teresa Logue, MPH, Miami/Dade County Health Department, Florida Department of Health; Raphael Mendoza, Broward County Health Department, Florida Department of Health; Amanda Feldpausch, MPH, Georgia Department of Public Health; Teri Graham, MPH, Georgia Department of Public Health; Sylvia Mann, MS, Hawaii Department of Health; Sarah Y. Park, MD, Hawaii Department of Health; Kris Kelly Carter, DVM, Idaho Division of Public Health, CDC, U.S. Public Health Service; Emily J. Potts, MPH, Indiana State Department of Health; Taryn Stevens, MPH, Indiana State Department of Health; Sean Simonson, MPH, Louisiana Department of Health; Julius L. Tonzel, MPH, Louisiana Department of Health; Shari Davis, MPH, Maine Center for Disease Control and Prevention; Sara Robinson, MPH, Maine Department of Health and Human Services; Judie K. Hyun, MHS, Maryland Department of Health and Mental Hygiene; Erin M. Jenkins, MPH, Maryland Department of Health and Mental Hygiene; Monika Piccardi, Maryland Department of Health and Mental Hygiene; Lawrence D. Reid, PhD, Maryland Department of Health and Mental Hygiene; Julie E. Dunn, PhD, Massachusetts Department of Public Health; Cathleen A. Higgins, Massachusetts Department of Public Health; Angela E. Lin, MD, Massachusetts General Hospital for Children; Gerlinde S. Munshi, MA, Massachusetts Department of Public Health; Kayleigh Sandhu, MPH, Massachusetts Department of Public Health; Sarah J. Scotland, MPH, Massachusetts Department of Public Health; Susan Soliva, MPH, Massachusetts Department of Public Health; Glenn Copeland, MBA, Michigan Department of Health and Human Services; Kimberly A. Signs, DVM, Michigan Department of Health and Human Services; Elizabeth Schiffman, MPH, MA, Minnesota Department of Health; Paul Byers, MD, Mississippi State Department of Health; Sheryl Hand, Mississippi State Department of Health; Christine L. Mulgrew, PhD, State of Montana; Jeff Hamik, MS, Division of Public Health, Nebraska Department of Health and Human Services; Samir Koirala, MSc, Division of Public Health, Nebraska Department of Health and Human Services; Lisa A. Ludwig, MD, Division of Public Health, Nebraska Department of Health and Human Services; Carolyn Rose Fredette, MPH, New Hampshire Department of Health and Human Services; Kristin Garafalo, MPH, New Jersey Department of Health; Karen Worthington, MS, New Jersey Department of Health; Abubakar Ropri, MPH, New Mexico State Department of Health; Julius Nchangtachi Ade, MD, DrPH, New York State Department of Health; Zahra S. Alaali, MPH, New York State Department of Health; Debra Blog, MD, New York State Department of Health; Scott J. Brunt, Wadsworth Center, New York State Department of Health; Patrick Bryant, PhD, Wadsworth Center, New York State Department of Health; Amy E. Burns, MS, New York State Department of Health; Steven Bush, MS, Wadsworth Center, New York State Department of Health; Kyle Carson, New York State Department of Health; Amy B. Dean, PhD, Wadsworth Center, New York State Department of Health; Valerie Demarest, Wadsworth Center, New York State Department of Health; Elizabeth M. Dufort, MD, New York State Department of Health; Alan P. Dupuis II, Wadsworth Center, New York State Department of Health; Ann Sullivan-Frohm, New York State Department of Health; Andrea Marias Furuya, PhD, Wadsworth Center, New York State Department of Health; Meghan Fuschino, MS, Wadsworth Center, New York State Department of Health; Viola H. Glaze, Health Research Inc; Jacquelin Griffin, New York State Department of Health; Christina Hidalgo, MPH, New York State Department of Health; Karen E. Kulas, Wadsworth Center, New York State Department of Health; Daryl M. Lamson, Wadsworth Center, New York State Department of Health; Lou Ann Lance, MSN, New York State Department of Health; William T. Lee, PhD, Wadsworth Center, New York State Department of Health; Ronald Limberger, PhD, Wadsworth Center, New York State Department of Health; Patricia S. Many, MS, New York State Department of Health; Mary J. Marchewka, Wadsworth Center, New York State Department of Health; Brenda Elizabeth Naizby, New York State Department of Health; MaryJo Polfleit, New York State Department of Health; Michael Popowich, Wadsworth Center, New York State Department of Health; Tabassum Rahman, MS, New York State Department of Health; Timothy Rem, New York State Department of Health; Amy E. Robbins, MPH, New York State Department of Health; Jemma V. Rowlands, MPH, New York State Department of Health; Chantelle Seaver, MS, New York State Department of Health; Kimberley A. Seward, MPH, New York State Department of Health; Lou Smith, MD, New York State Department of Health; Inderbir Sohi, MSPH, New York State Department of Health; Kirsten St. George, PhD, Wadsworth Center, New York State Department of Health; Maria I. Souto, MPH, Rockland County Department of Health; Rachel Elizabeth Wester, MPH, New York State Department of Health; Susan J. Wong, PhD, Wadsworth Center, New York State Department of Health; Li Zeng, Wadsworth Center, New York State Department of Health; Joel Ackelsberg, MD, New York City Department of Health & Mental Hygiene; Byron Alex, MD, New York City Department of Health & Mental Hygiene; Vennus Ballen, MD, New York City Department of Health & Mental Hygiene; Jennifer Baumgartner, MSPH, New York City Department of Health & Mental Hygiene; Danielle Bloch, MPH, New York City Department of Health & Mental Hygiene; Sandhya Clark, MPH, New York City Department of Health & Mental Hygiene; Erin Conners, PhD, New York City Department of Health & Mental Hygiene; Hannah Cooper, MBChB, New York City Department of Health & Mental Hygiene; Alexander Davidson, MPH, New York City Department of Health & Mental Hygiene; Catherine Dentinger, MS, MPH, New York City Department of Health & Mental Hygiene; Bisram Deocharan, PhD, New York City Department of Health & Mental Hygiene; Andrea DeVito, MPH, New York City Department of Health & Mental Hygiene; Jie Fu, PhD, New York City Department of Health & Mental Hygiene; Gili Hrusa, MPH, New York City Department of Health & Mental Hygiene; Maryam Iqbal, MS, New York City Department of Health & Mental Hygiene; Martha Iwamoto, MD, New York City Department of Health & Mental Hygiene; Lucretia Jones, DrPH, New York City Department of Health & Mental Hygiene; Hannah Kubinson, MPH, New York City Department of Health & Mental Hygiene; Maura Lash, MPH, New York City Department of Health & Mental Hygiene; Marcelle Layton, MD, New York City Department of Health & Mental Hygiene; Christopher T. Lee, MD, New York City Department of Health & Mental Hygiene; Dakai Liu, PhD, New York City Department of Health & Mental Hygiene; Emily McGibbon, MPH, New York City Department of Health & Mental Hygiene; Morgan Moy, MPH, New York City Department of Health & Mental Hygiene; Stephanie Ngai, MPH, New York City Department of Health & Mental Hygiene; Hilary B. Parton, MPH, New York City Department of Health & Mental Hygiene; Eric Peterson, MPH, New York City Department of Health & Mental Hygiene; Jose Poy, MPH, New York City Department of Health & Mental Hygiene; Jennifer Rakeman, PhD, New York City Department of Health & Mental Hygiene; Alaina Stoute, MPH, New York City Department of Health & Mental Hygiene; Corinne Thompson, PhD, New York City Department of Health & Mental Hygiene; Don Weiss, MD, New York City Department of Health & Mental Hygiene; Emily Westheimer, MSc, New York City Department of Health & Mental Hygiene; Ann Winters, MD, New York City Department of Health & Mental Hygiene; Mohammad Younis, MS, MPA, New York City Department of Health & Mental Hygiene; Ronna L. Chan, PhD, North Carolina Department of Health and Human Services, Division of Public Health; Laura Jean Cronquist, North Dakota Department of Health, Division of Disease Control; Lisa Caton, MS, Oklahoma State Department of Health; Leah Lind, MPH, Pennsylvania Department of Health; Kumar Nalluswami, MD, Pennsylvania Department of Health; Dana Perella, MPH, Philadelphia Department of Public Health; Diane S. Brady, MS, Rhode Island Department of Health; Michael Gosciminski, MPH, Rhode Island Department of Health; Patricia McAuley, MSN, Rhode Island Department of Health; Daniel Drociuk, MT, South Carolina Department of Health & Environmental Control, Division of Acute Disease Epidemiology; Vinita Leedom, MPH, South Carolina Department of Health & Environmental Control, Division of Maternal and Child Health; Brian Witrick, MPH, South Carolina Department of Health & Environmental Control, Division of Acute Disease Epidemiology; Jan Bollock, South Dakota Department of Health DIS; Marie Bottomley Hartel, MPH, Tennessee Department of Health; Loraine Swanson Lucinski, MPH, Tennessee Department of Health; Morgan McDonald, MD, Tennessee Department of Health; Angela M. Miller, PhD, Tennessee Department of Health; Tori Armand Ponson, MPH, Tennessee Department of Health; Laura Price, Tennessee Department of Health; Amy E. Nance, MPH, Utah Birth Defect Network, Utah Department of Health; Dallin Peterson, Utah Department of Health; Sally Cook, Vermont Department of Health; Brennan Martin, MPH, Vermont Department of Health; Hanna Oltean, MPH, Washington State Department of Health; Jillian Neary, MPH, Washington State Department of Health; Melissa A. Baker, MA, West Virginia Office of Maternal, Child and Family Health; Kathy Cummons, MSW, West Virginia Office of Maternal, Child and Family Health; Katie Bryan, MPH, Wyoming Department of Health; Kathryn E. Arnold, MD, CDC; Annelise C. Arth, MPH, CDC; Brigid C. Bollweg, MPH, CDC; Janet D. Cragan, MD, CDC; April L. Dawson, MPH, CDC; Amy M. Denison, PhD, CDC; Eric J. Dziuban, MD, CDC; Lindsey Estetter, MS, CDC; Luciana Silva-Flannery, PhD, CDC; Rebecca J. Free, MD, CDC; Romeo R. Galang, MD, CDC; Joy Gary, DVM, PhD, CDC; Cynthia S. Goldsmith, MGS, CDC; Caitlin Green, MPH, CDC; Gillian L. Hale, MD, CDC; Heather M. Hayes, CDC; Irogue Igbinosa, MD, CDC; M. Kelly Keating, DVM, CDC; Sumaiya Khan, MPH, CDC, ORISE; Shin Y. Kim, MPH, CDC; Margaret Lampe, MPH, CDC; Amanda Lewis, CDC; Cara Mai, PhD, CDC; Roosecelis Brasil Martines, MD, PhD, CDC; Brooke Miers, MS, CDC; Jazmyn Moore, MPH, CDC; Atis Muehlenbachs, MD, PhD, CDC; John Nahabedian, MS, CDC; Amanda Panella, MPH, CDC; Vaunita Parihar, CDC; Mitesh M. Patel, CDC; D. Brett Rabeneck, MS, CDC; Sonja A. Rasmussen, MD, CDC; Jana M. Ritter, DVM, CDC; Dominique C. Rollin, MD, CDC; Jeanine H. Sanders, CDC; Wun-Ju Shieh, MD, PhD, CDC; Regina M. Simeone, MPH, CDC; Elizabeth L. Simon, MPH, CDC; John R. Sims, CDC; Pamela J. Spivey, CDC; Helen Talley-McRae, CDC; Alphonse K. Tshiwala, MPA, CDC; Kelley VanMaldeghem, MPH, CDC; Laura Viens, MD, CDC; Anne Wainscott-Sargent, Carter Consulting; Tonya Williams, PhD, CDC; Sherif Zaki, MD, PhD, CDC; all of these individuals meet collaborator criteria.
  18. Conclusions and Comments The number of pregnant women with laboratory evidence of possible recent Zika virus infection and the number of fetuses/infants with Zika virus–associated birth defects continues to increase in the United States. The proportion of fetuses and infants with birth defects among pregnancies with confirmed Zika virus infection at any time during pregnancy was more than 30 times higher than the baseline prevalence in the pre-Zika years, and a higher proportion of those with first trimester infections had birth defects (4). Although microcephaly was the first recognized birth defect reported in association with congenital Zika virus infection, Zika virus–associated brain abnormalities can occur without microcephaly, and neuroimaging is needed to detect these abnormalities (9). Neuroimaging is also used in other congenital infections to identify brain abnormalities; for example, neuroimaging findings in infants with congenital cytomegalovirus infection are correlated with neurodevelopmental outcomes (10). Postnatal neuroimaging is recommended for all infants born to women with laboratory evidence of Zika virus infection to identify infants with brain anomalies that warrant additional evaluation to ensure that appropriate intervention is provided (8). Based on data reported to the USZPR, the majority of these infants had not received recommended neuroimaging. In addition to infants with birth defects, complete follow-up and routine developmental assessment of all infants born to women with laboratory evidence of possible recent Zika virus infection is essential to help identify future outcomes potentially associated with congenital Zika virus infection and ensure that the referrals to appropriate support and follow-up care are made. The findings in this report are subject to at least four limitations. First, selection bias might affect which pregnancies are reported to the USZPR, because pregnant women with symptoms of Zika virus disease might be more likely than asymptomatic women to be tested. Pregnant women with Zika virus exposure and prenatally detected fetal abnormalities or infants with birth defects might be more likely to be tested for Zika virus infection. In addition, pregnancies resulting in a loss might be more likely to have had a confirmed Zika virus infection and more likely to have the placenta or other pathologic specimens tested (11). However, it is also possible that birth defects in pregnancy losses, including stillbirths, have not been reported. Second, while CDC has worked closely with state and local health departments to obtain complete information, delays in reporting postnatal neuroimaging or infant Zika virus testing results are possible. In addition, some of the pregnancies included in the analysis were completed before CDC’s most recent infant guidance (8) was released, and thus, current recommendations for neuroimaging or testing might not have been implemented. Third, current testing methodologies are limited in that they can only identify recent Zika virus infections (5) and might miss those women who are tested when Zika virus RNA and/or IgM is no longer detectable; these pregnancies would not be included in the USZPR unless the fetus/infant or placenta has a positive Zika virus test result. Also, serologic testing cannot readily discriminate between flaviviruses because of crossreactivity (5); therefore, some pregnancies in the USZPR might have had a recent infection with a flavivirus other than Zika virus which could lead to an underestimate of the proportion of fetuses/infants affected. For this reason, in this report, analysis of the subset of pregnancies with laboratory-confirmed recent Zika virus infection was included. Finally, limited data are available about other maternal risk factors for birth defects, including genetic or other infectious causes, which might be causal factors for a few of the birth defects reported here. These findings underscore the serious risk for birth defects posed by Zika virus infection during pregnancy and highlight why pregnant women should avoid Zika virus exposure and that all pregnant women should be screened for possible Zika virus exposure at every prenatal visit, with testing of pregnant women and infants in accordance with current guidance (https://www.cdc.gov/zika/pdfs/zikapreg_screeningtool.pdf) (8,12). Zika virus testing of infants is recommended for 1) all infants born to women with laboratory evidence of Zika virus infection in pregnancy and 2) infants with findings suggestive of congenital Zika syndrome born to women with an epidemiologic link suggesting possible transmission, regardless of maternal testing results. Infants without abnormalities born to women with an epidemiological link suggesting possible Zika virus exposure during pregnancy, and for whom maternal testing was not performed or was performed more than 12 weeks after exposure, should have a comprehensive exam. If there is concern about infant follow-up or maternal testing is not performed, infant Zika virus testing should be considered. The initial evaluation of infants should include a comprehensive physical examination, including a neurologic examination, postnatal neuroimaging, and standard newborn hearing screen. Additional evaluation might be considered based on clinical and laboratory findings, however routine developmental assessment is recommended as part of pediatric care (8). Based on initial USZPR reports, most infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy might not be receiving the recommended evaluation (e.g., postnatal neuroimaging). CDC is working with public health officials, professional societies, and health care providers to increase awareness of and adherence to CDC guidance for the evaluation and management of infants with possible congenital Zika virus infection. Identification and follow-up care of infants born to mothers with laboratory evidence of possible recent Zika virus infection during pregnancy and infants with possible congenital Zika virus infection can ensure that appropriate intervention services are available to affected infants.
  19. Results From January 15 through December 27, 2016, a total of 1,297 pregnancies with possible recent Zika virus infection were reported to the USZPR from 44 states ( Figure 1), including 972 completed pregnancies with reported outcomes (895 liveborn infants and 77 pregnancy losses). Among the completed pregnancies, 599 (62%) pregnant women were asymptomatic, 348 (36%) were symptomatic, and 25 (3%) had missing symptom information ( Table 1). Birth defects were reported for 51 (5%) of the 972 completed pregnancies with laboratory evidence of possible recent Zika virus infection. The proportion was higher among completed pregnancies with confirmed Zika virus infection (24/250, 10%). Among completed pregnancies with confirmed Zika virus infection, 217 of 250 (87%) tested positive by RT-PCR, including 24 pregnancies with a fetus or infant with birth defects. Birth defects were reported in similar proportions of fetuses/infants whose mothers did and did not report symptoms of Zika virus disease during pregnancy. Brain abnormalities and/or microcephaly were reported in 43 (84%) of 51 fetuses/infants with birth defects. Among pregnancies with confirmed Zika virus infection, brain abnormalities and/or microcephaly were reported in 18 (75%) of 24 fetuses/infants with birth defects. The 51 fetuses or infants with birth defects were from pregnancies with Zika virus exposure from the following 16 countries/territories with active Zika virus transmission: Barbados, Belize, Brazil, Cape Verde, Colombia, Dominican Republic, El Salvador, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Puerto Rico, Republic of Marshall Islands, and Venezuela. Birth defects were reported in a higher proportion of fetuses or infants whose mothers were infected during the first trimester of pregnancy. Among 157 pregnancies in which women had symptom onset or exposure to Zika virus infection during the first trimester, 14 (9%) fetuses/infants had reported birth defects (Table 1). When pregnancies with symptom onset or exposure during first trimester were limited to those with laboratory-confirmed Zika virus infection, nine (15%) of 60 completed pregnancies had reported birth defects. Among the 895 liveborn infants, postnatal neuroimaging results were reported to the USZPR for 221 (25%). Zika virus testing results of any specimen were reported for 585 (65%) infants; 94 (11%) of all 895 liveborn infants had positive Zika virus test results. Among the 45 liveborn infants with birth defects, 25 (56%) had positive infant Zika virus testing results reported, and 29 (64%) had postnatal neuroimaging reported to the USZPR ( Table 2). Among the 850 liveborn infants without birth defects, 69 (8%) had positive infant Zika virus testing results reported, and 192 (23%) had postnatal neuroimaging reported to the USZPR. The percentage of infants reported to have received postnatal neuroimaging was 20% among 406 born through August 2016, and 28% among 489 born during September–December 2016, after the updated CDC guidance was released (8) ( Figure 2).
  20. Methods The USZPR defines laboratory evidence of possible recent Zika virus infection as 1) recent Zika virus infection detected by a Zika virus RNA nucleic acid test (NAT, e.g., reverse transcription–polymerase chain reaction [RT-PCR]) on any maternal, placental, or fetal/infant specimen or 2) detection of recent Zika virus infection or recent unspecified flavivirus infection by serologic tests on a maternal or infant specimen (i.e., either positive or equivocal Zika virus immunoglobulin M [IgM] AND Zika virus plaque reduction neutralization test [PRNT] titer ≥10, regardless of dengue virus PRNT value; or negative Zika virus IgM, AND positive or equivocal dengue virus IgM, AND Zika virus PRNT titer ≥10, regardless of dengue virus PRNT titer). Infants with positive or equivocal Zika virus IgM are included, provided a confirmatory PRNT has been performed on a maternal or infant specimen. The USZPR laboratory inclusion criteria are specified as “possible” recent Zika virus infection because the USZPR includes mother-infant pairs with serological evidence of a recent unspecified flavivirus infection, as well as those with laboratory-confirmed Zika virus infection. Analyses were done on both the overall completed pregnancies in the USZPR from the 50 U.S. states and DC and a subset of completed pregnancies that demonstrated confirmed recent Zika virus infection (5,6). These are pregnancies in which the presence of Zika virus RNA in a maternal, placental, or fetal/infant specimen was documented by a positive NAT, or in which Zika virus IgM was positive or equivocal and Zika virus PRNT titer was ≥10 and dengue virus PRNT was <10. Among symptomatic women, gestational timing of Zika virus infection was calculated using symptom onset date. Among asymptomatic women, the trimester of exposure was calculated using dates of travel to areas of active Zika virus transmission or sexual exposure. First trimester exposure was classified into two categories: 1) women with symptoms or exposure in the first trimester only§ (defined as first trimester or first trimester and periconceptional period); and 2) women with exposure during multiple trimesters including the first trimester. Estimates were not calculated for exposure in other trimesters because of small numbers. Pregnant women who did not have first trimester exposure might have had exposure in the periconceptional period only, second trimester, third trimester, or both the second and third trimester; for many women, the information on trimester of exposure was missing. The Zika virus–associated birth defects (henceforth referred to as “birth defects”) were analyzed in two mutually exclusive categories: 1) brain abnormalities and/or microcephaly regardless of the presence of additional birth defects, and 2) neural tube defects and other early brain malformations, eye abnormalities, and other consequences of central nervous system dysfunction, among fetuses and infants without evident brain abnormalities or microcephaly (7). Clinical experts reviewed reported information to ensure that each fetus or infant with birth defects met the criteria of the USZPR case definition. The proportion of fetuses or infants with birth defects among completed pregnancies was estimated among asymptomatic and symptomatic pregnant women, and women with first trimester exposure, using the Wilson score interval and 95% CI for a binomial proportion. Outcomes from multiple gestation pregnancies were counted once. Separate estimates were calculated for pregnancies with any laboratory evidence of recent Zika virus infection and for the subset of pregnancies with laboratory-confirmed recent Zika virus infection. For all liveborn infants with and without birth defects, the proportion who had any reported postnatal neuroimaging (cranial ultrasound, computed tomography, or magnetic resonance imaging) was calculated, as well as the proportion who had laboratory testing for Zika virus reported on an infant specimen. CDC released updated Interim Guidance for the Evaluation and Management of Infants with Possible Congenital Zika Virus Infection in August 2016 (8), which stated that postnatal neuroimaging and testing should be routine for all infants born to women with laboratory evidence of Zika virus infection during pregnancy; the proportion of infants with neuroimaging performed was calculated before and after this guidance was released.
  21. Introduction In response to the outbreak of Zika virus in the World Health Organization Region of the Americas and concerns about birth defects linked to Zika virus infection during pregnancy, CDC issued a travel notice on January 15, 2016, advising pregnant women to consider postponing travel to areas with active transmission of Zika virus. As part of the initial phase of the emergency response, CDC collaborated with state, tribal, local, and territorial health departments to establish the U.S. Zika Pregnancy Registry (USZPR) as an enhanced national surveillance system to monitor pregnancy and fetal/infant outcomes among pregnancies with laboratory evidence of possible recent Zika virus infection (1). The USZPR includes data on pregnant women and their infants at birth and at ages 2, 6, and 12 months. The USZPR includes data from all 50 states, DC, and all U.S. territories except Puerto Rico; pregnancies in Puerto Rico are monitored separately by the Zika Active Pregnancy Surveillance System (2). To be included in the USZPR, either the pregnant woman, placenta, or fetus/infant must have laboratory evidence of possible recent Zika virus infection. Pregnant women in the United States and U.S. territories (with the exception of Puerto Rico) with laboratory evidence of possible recent Zika virus infection (regardless of whether they have symptoms) and the periconceptionally,* prenatally, or perinatally exposed infants born to these women are eligible to be included. The USZPR also includes infants with laboratory evidence of possible congenital Zika virus infection (regardless of whether they have symptoms or findings at birth) and their mothers. This report updates the previous report (3) from the USZPR and provides data on pregnancies completed in the 50 U.S. states and DC from December 1, 2015 through December 27, 2016, reported to CDC from January 15, 2016, through March 14, 2017.† Completed pregnancies include those of any length of gestation that end in a liveborn infant or a pregnancy loss. The baseline prevalence of defects consistent with those that have been observed with congenital Zika virus infection was approximately 2.9 per 1,000 live births in the pre-Zika years (4). The initial findings from the USZPR represent an approximate twentyfold increase in Zika virus–associated birth defects among pregnant women with laboratory evidence of possible recent Zika virus infection, with an approximate thirtyfold increase in brain abnormalities and/or microcephaly. Updated data in this report can also be compared with this benchmark (3,4).
  22. Abstract Background: In collaboration with state, tribal, local, and territorial health departments, CDC established the U.S. Zika Pregnancy Registry (USZPR) in early 2016 to monitor pregnant women with laboratory evidence of possible recent Zika virus infection and their infants. Methods: This report includes an analysis of completed pregnancies (which include live births and pregnancy losses, regardless of gestational age) in the 50 U.S. states and the District of Columbia (DC) with laboratory evidence of possible recent Zika virus infection reported to the USZPR from January 15 to December 27, 2016. Birth defects potentially associated with Zika virus infection during pregnancy include brain abnormalities and/or microcephaly, eye abnormalities, other consequences of central nervous system dysfunction, and neural tube defects and other early brain malformations. Results: During the analysis period, 1,297 pregnant women in 44 states were reported to the USZPR. Zika virus–associated birth defects were reported for 51 (5%) of the 972 fetuses/infants from completed pregnancies with laboratory evidence of possible recent Zika virus infection (95% confidence interval [CI] = 4%–7%); the proportion was higher when restricted to pregnancies with laboratory-confirmed Zika virus infection (24/250 completed pregnancies [10%, 95% CI = 7%–14%]). Birth defects were reported in 15% (95% CI = 8%–26%) of fetuses/infants of completed pregnancies with confirmed Zika virus infection in the first trimester. Among 895 liveborn infants from pregnancies with possible recent Zika virus infection, postnatal neuroimaging was reported for 221 (25%), and Zika virus testing of at least one infant specimen was reported for 585 (65%). Conclusions and Implications for Public Health Practice: These findings highlight why pregnant women should avoid Zika virus exposure. Because the full clinical spectrum of congenital Zika virus infection is not yet known, all infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy should receive postnatal neuroimaging and Zika virus testing in addition to a comprehensive newborn physical exam and hearing screen. Identification and follow-up care of infants born to women with laboratory evidence of possible recent Zika virus infection during pregnancy and infants with possible congenital Zika virus infection can ensure that appropriate clinical services are available.
  23. Key Points • In 2016, a total of 1,297 pregnancies with possible recent Zika virus infection were reported to the U.S. Zika Pregnancy Registry from 44 states. • Approximately one in 10 pregnancies with laboratory-confirmed Zika virus infection resulted in a fetus or infant with Zika virus–associated birth defects. • The proportion of fetuses and infants with Zika virus–associated birth defects was highest among those with first trimester Zika virus infections. • Only 25% of infants from pregnancies with possible recent Zika virus infection reported receiving postnatal neuroimaging. • Identification and follow-up care of infants born to mothers with laboratory evidence of possible recent Zika virus infection during pregnancy and infants with congenital Zika virus infection can ensure that appropriate intervention services are available to affected infants. • Additional information is available at https://www.cdc.gov/vitalsigns/.
  24. Megan R. Reynolds, MPH1; Abbey M. Jones, MPH1; Emily E. Petersen, MD2; Ellen H. Lee, MD3; Marion E. Rice, MPH1,4; Andrea Bingham, PhD5; Sascha R. Ellington, MSPH2; Nicole Evert, MS6; Sarah Reagan-Steiner, MD7; Titilope Oduyebo, MD2; Catherine M. Brown, DVM8; Stacey Martin, MSc9; Nina Ahmad, MD10; Julu Bhatnagar, PhD7; Jennifer Macdonald, MPH11; Carolyn Gould, MD9; Anne D. Fine, MD3; Kara D. Polen, MPH1; Heather Lake-Burger, MPH5; Christina L. Hillard, MA1; Noemi Hall, PhD6,12; Mahsa M. Yazdy, PhD8; Karnesha Slaughter, MPH1; Jamie N. Sommer, MS10; Alys Adamski, PhD1; Meghan Raycraft, MPH1; Shannon Fleck-Derderian, MPH4,13; Jyoti Gupta, MPH11; Kimberly Newsome, MPH1; Madelyn Baez-Santiago, PhD1; Sally Slavinski, DVM3; Jennifer L. White, MPH10; Cynthia A. Moore, MD, PhD1; Carrie K. Shapiro-Mendoza, PhD2; Lyle Petersen, MD9; Coleen Boyle, PhD14; Denise J. Jamieson, MD2; Dana Meaney-Delman, MD13; Margaret A. Honein, PhD1; U.S. Zika Pregnancy Registry Collaboration Corresponding author: Margaret A. Honein, eocbirthdef@cdc.gov, 404-639-3286. Top 1Division of Congenital and Developmental Disorders, National Center on Birth Defects and Developmental Disabilities, CDC; 2Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC; 3New York City Department of Health & Mental Hygiene; 4Oak Ridge Institute for Science and Education; 5Florida Department of Health; 6Texas Department of State Health Services; 7Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC; 8Massachusetts Department of Public Health; 9Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, CDC; 10New York State Department of Health; 11Virginia Department of Health; 12Epidemic Intelligence Service, CDC; 13Office of the Director, National Center for Emerging and Zoonotic Infectious Diseases, CDC; 14Office of the Director, National Center on Birth Defects and Developmental Disabilities, CDC.