Zika in Infants and Pregnancy (ZIP)

• ClinicalTrials.gov Identifier: NCT02856984
• Recruitment Status: Completed
• First Posted: August 5, 2016
• Last Update Posted: August 19, 2021
• Sponsor: RTI International
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Environmental Health Sciences (NIEHS); Oswaldo Cruz Foundation
• Information provided by (Responsible Party): RTI International

Study Description

Brief Summary:

The overall objective of this multisite, multicountry Zika in Infants and Pregnancy (ZIP) study is to assess the strength of the association between Zika virus infection (ZIKV) during pregnancy and adverse maternal/fetal outcomes and the risk of vertical transmission. The study will prospectively enroll a cohort of pregnant women up to 17 weeks and 6 days gestation and subjects at any gestational age with acute Zika infection, confirmed by serology or PCR (polymerase chain reaction) test. The study will follow these women through their pregnancy to identify for clinical evidence of acute ZIKV, while controlling for potential confounders. Outcomes in the women, the developing fetus, and infants will be assessed. All protocol-specified data will be recorded and entered in a central data management system for the purposes of analysis of composite data from the study.

Condition or disease
Zika Virus Disease (Disorder)

Detailed Description:

The overall objective of this multisite, multicountry Zika in Infants and Pregnancy (ZIP) study is to assess the strength of the association between Zika virus infection (ZIKV) during pregnancy and adverse maternal/fetal outcomes and the risk of vertical transmission. The study will prospectively enroll a cohort of pregnant women up to 17 weeks and 6 days gestation and subjects at any gestational age with acute Zika infection, confirmed by serology or PCR (polymerase chain reaction) test. The study will follow these women through their pregnancy to identify for clinical evidence of acute ZIKV, while controlling for potential confounders. Outcomes in the women, the developing fetus, and infants will be assessed. All protocol-specified data will be recorded and entered in a central data management system for the purposes of analysis of composite data from the study.

The study will recruit up to10,000 pregnant women in their first trimester from ZIKV-endemic regions and follow them longitudinally to study the impact of incident ZIKV during pregnancy on maternal, fetal, and newborn outcomes. Researchers will identify cases of incident ZIKV among pregnant women by monitoring for symptoms of Zika-like illness and performing serial laboratory sampling for diagnosis of seroconversion and viral shedding. After delivery, infants born with evidence of ZIKV or born to mothers diagnosed with incident virus infection will be followed in a prospective longitudinal cohort for at least 1 year. In addition, a control group of infants born to mothers without evidence of ZIKV during pregnancy will be followed.

Study Design

• Study Type: Observational
• Actual Enrollment: 6461 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: International Prospective Observational Cohort Study of Zika in Infants
• Study Start Date: June 2016
• Actual Primary Completion Date: May 5, 2020
• Actual Study Completion Date: May 5, 2020

Groups and Cohorts

Group/Cohort
ZIKV infected women; The study will prospectively enroll pregnant women up to 17 weeks and 6 days gestation and follow them through their pregnancy for clinical evidence of acute ZIKV infection while controlling for potential confounders. All pregnant women will be followed throughout the pregnancy, delivery, and 6 weeks postpartum. Outcomes in women, the developing fetus, and infants will be assessed.
Control (uninfected women); The women who remain uninfected will serve as the internal comparison group. The infants who remain uninfected at delivery and throughout the follow-up period will serve as the internal comparison group.

Outcome Measures

Primary Outcome Measures :

1. Incidence of congenital malformations for ZIKV infected participants [ Time Frame: Time of birth of infant ]
   To measure the incidence of congenital malformations in fetuses/infants.
2. Incidence of congenital malformations for ZIKV infected participants [ Time Frame: 3 months of age ]
   To measure the incidence of congenital malformations in fetuses/infants.
3. Incidence of congenital malformations for ZIKV infected participants [ Time Frame: 6 months of age ]
   To measure the incidence of congenital malformations in fetuses/infants.
4. Incidence of congenital malformations for ZIKV infected participants [ Time Frame: 12 months of age ]
   To measure the incidence of congenital malformations in fetuses/infants.
5. Incidence of adverse fetal outcomes for ZIKV infected participants [ Time Frame: Time of birth of infant ]
   To measure the incidence of adverse fetal outcomes (including microcephaly, fetal demise, neonatal death, central nervous system (CNS) malformations, hydrops, and ocular abnormalities) in fetuses/infants.
6. Incidence of adverse fetal outcomes for ZIKV infected participants [ Time Frame: 3 months of age ]
   To measure the incidence of adverse fetal outcomes (including microcephaly, fetal demise, neonatal death, central nervous system (CNS) malformations, hydrops, and ocular abnormalities) in fetuses/infants.
7. Incidence of adverse fetal outcomes for ZIKV infected participants [ Time Frame: 6 months of age ]
   To measure the incidence of adverse fetal outcomes (including microcephaly, fetal demise, neonatal death, central nervous system (CNS) malformations, hydrops, and ocular abnormalities) in fetuses/infants.
8. Incidence of adverse fetal outcomes for ZIKV infected participants [ Time Frame: 12 months of age ]
   To measure the incidence of adverse fetal outcomes (including microcephaly, fetal demise, neonatal death, central nervous system (CNS) malformations, hydrops, and ocular abnormalities) in fetuses/infants.
9. Incidence of congenital malformations for ZIKV symptomatic participants [ Time Frame: Time of birth of infant ]
   To measure the incidence of congenital malformations in fetuses/infants.
10. Incidence of congenital malformations for ZIKV symptomatic participants [ Time Frame: 3 months of age ]
    To measure the incidence of congenital malformations in fetuses/infants.
11. Incidence of congenital malformations for ZIKV symptomatic participants [ Time Frame: 6 months of age ]
    To measure the incidence of congenital malformations in fetuses/infants.
12. Incidence of congenital malformations for ZIKV symptomatic participants [ Time Frame: 12 months of age ]
    To measure the incidence of congenital malformations in fetuses/infants.
13. Incidence of adverse fetal outcomes for ZIKV symptomatic participants [ Time Frame: Time of birth of infant ]
    To measure the incidence of adverse fetal outcomes (including microcephaly, fetal demise, neonatal death, CNS malformations, hydrops, and ocular abnormalities) in fetuses/infants.
14. Incidence of adverse fetal outcomes for ZIKV symptomatic participants [ Time Frame: 3 months of age ]
    To measure the incidence of adverse fetal outcomes (including microcephaly, fetal demise, neonatal death, CNS malformations, hydrops, and ocular abnormalities) in fetuses/infants.
15. Incidence of adverse fetal outcomes for ZIKV symptomatic participants [ Time Frame: 6 months of age ]
    To measure the incidence of adverse fetal outcomes (including microcephaly, fetal demise, neonatal death, CNS malformations, hydrops, and ocular abnormalities) in fetuses/infants.
16. Incidence of adverse fetal outcomes for ZIKV symptomatic participants [ Time Frame: 12 months of age ]
    To measure the incidence of adverse fetal outcomes (including microcephaly, fetal demise, neonatal death, CNS malformations, hydrops, and ocular abnormalities) in fetuses/infants.

Biospecimen Retention:   Samples Without DNA

maternal samples from urine, blood, genital secretions, saliva, and breast milk, and when available amniotic fluid and tissue; infant urine, blood, and saliva

Eligibility Criteria

• Ages Eligible for Study: 15 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes
• Sampling Method: Probability Sample

Study Population

The study will recruit up to 10,000 pregnant women up to 17 weeks and 6 days gestation and subjects at any gestational age with acute Zika infection, confirmed by serology or PCR (polymerase chain reaction) test from ZIKV-endemic regions and follow them longitudinally to study the impact of incident ZIKV during pregnancy on maternal, fetal, and newborn outcomes. Researchers will identify cases of incident ZIKV among pregnant women by monitoring for symptoms of Zika-like illness and performing serial laboratory sampling for diagnosis of seroconversion and viral shedding. After delivery, infants born with evidence of ZIKV or born to mothers diagnosed with incident virus infection will be followed in a prospective longitudinal cohort for at least 1 year. In addition, a control group of infants born to mothers without evidence of ZIKV during pregnancy will be followed.

Criteria

Inclusion Criteria:

• Informed consent
• Age >15 years
• Assent and consent as required per local country regulations
• Confirmation of pregnancy by beta human chorionic gonadotropin (hCG) measurement in blood/urine or ultrasound confirmation of pregnancy with fetal heart tones present
• Pregnant women up to 17 weeks and 6 days gestation and subjects at any gestational age with acute Zika infection, confirmed by serology or PCR (polymerase chain reaction) test.

Exclusion Criteria: Pregnant Women

• Women who cannot adhere to proposed testing schedule
• Pregnant women enrolled in other research including other ZIKV research

Inclusion Criteria (newborn)

• All infants born to women enrolled in the observational cohort are eligible for enrollment

Exclusion Criteria (newborn)

• Mother or custodial parent does not consent to have child participate
• Infants born to mothers that are not part of the ZIP cohort study

Contacts and Locations

Locations

Brazil

Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz/MS; Rue Waldemar Falcao

Salvador, Bahia, Brazil, 40296-710

Departamento de Medicina Tropical da Universidade Federal de Pernambuco-UFPE

Recife, PE, Brazil, CEP: 50670-901

Instituto Fernandes Figueira - FIOCRUZ

Rio de Janeiro, RJ, Brazil, 22250-020

Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900 - Monte Alegre

Ribeirão Preto, SP, Brazil, 14049-900

Colombia

Centro Medico Imbanaco

Cali, Colombia

Guatemala

Fundación para la Alimentación y Nutrición de Centro América y Panamá (INCAP)

Guatemala, Guatemala

Nicaragua

MINSA Central

Managua, Nicaragua, 16064

Peru

Universidad Peruana

Lima, Peru

Puerto Rico

University of Puerto Rico Medical Sciences Campus

San Juan, Puerto Rico, 00921

University of Puerto Rico - Recinto de Río Piedras

San Juan, Puerto Rico, 00936

Sponsors and Collaborators

RTI International

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Environmental Health Sciences (NIEHS)

Oswaldo Cruz Foundation

Investigators

• Principal Investigator: Ricardo Ximenes, MD; Departamento de Medicina Tropical da Universidade Federal de Pernambuco-UFPE
• Principal Investigator: William Britt, MD; University of Alabama Birmingham School of Medicine
• Principal Investigator: Marisa Mussi, MD; Ribeirão Preto Medical School, University of São Paulo
• Principal Investigator: Albert Ko, MD; Yale University, Laboratory of Epidemiology and Public Health
• Principal Investigator: Deolinda Scalabrin; Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz/MS
• Principal Investigator: Marisa Elisabeth Lopes; Instituto Fernandes Figueira - FIOCRUZ
• Principal Investigator: Ana Garces, MD; Fundación para la Alimentación y Nutrición de Centro América y Panamá (INCAP)
• Principal Investigator: Jose Cordero, MD; University of Georgia
• Principal Investigator: Carmen Milagros Velez Vega, PhD; University of Puerto Rico
• Principal Investigator: George Seage, MD; Harvard University School of Public Health
• Principal Investigator: Carmen Zorilla, MD; University of Puerto Rico
• Principal Investigator: Eva Harris, PhD; University of Californina Berkeley
• Principal Investigator: Angel Balmaseda; MINSA Central
• Principal Investigator: Juan F Arias, MD; St. Jude Children's Research Hospital
• Principal Investigator: Jill Lebov, PhD; RTI International
• Principal Investigator: Teresa Ochoa Woodell, PhD; Universidad Peruana Cayetano Heredia

More Information

Publications:

WHO statement on the first meeting of the International Health Regulations (2005) (IHR 2005) Emergency Committee on Zika virus and observed increase in neurological disorders and neonatal malformations; 1 February 2016. Available at http://www.who.int/ mediacentre/news/statements/2016/1st-emergency-committee-zika/en/

Petersen EE, Staples JE, Meaney-Delman D, Fischer M, Ellington SR, Callaghan WM, Jamieson DJ. Interim Guidelines for Pregnant Women During a Zika Virus Outbreak--United States, 2016. MMWR Morb Mortal Wkly Rep. 2016 Jan 22;65(2):30-3. doi: 10.15585/mmwr.mm6502e1.

Powles R, Smith C, Milan S, Treleaven J, Millar J, McElwain T, Gordon-Smith E, Milliken S, Tiley C. Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: double-blind, placebo-controlled trial. Lancet. 1990 Dec 8;336(8728):1417-20. doi: 10.1016/0140-6736(90)93111-2.

CDC. Chikungunya virus. Atlanta, GA: US Department of Health and Human Services, CDC; 2015. http://www.cdc.gov/chikungunya/hc/clinicalevaluation.html

Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. Geneva: World Health Organization; 2009. Available from http://www.ncbi.nlm.nih.gov/books/NBK143157/

CDC Zika Virus; Areas with Zika http://www.cdc.gov/zika/geo/index.html

Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol. 2016 Jan;47(1):6-7. doi: 10.1002/uog.15831. No abstract available.

CDC. West Nile virus: insect repellent use & safety. Atlanta, GA: US Department of Health and Human Services, CDC; 2015. http://www.cdc.gov/westnile/faq/repellent.html.

CDC. Zika virus. Atlanta, GA: US Department of Health and Human Services, CDC; 2015. http://www.cdc.gov/zika/index.html

Oduyebo T, Petersen EE, Rasmussen SA, Mead PS, Meaney-Delman D, Renquist CM, Ellington SR, Fischer M, Staples JE, Powers AM, Villanueva J, Galang RR, Dieke A, Munoz JL, Honein MA, Jamieson DJ. Update: Interim Guidelines for Health Care Providers Caring for Pregnant Women and Women of Reproductive Age with Possible Zika Virus Exposure - United States, 2016. MMWR Morb Mortal Wkly Rep. 2016 Feb 12;65(5):122-7. doi: 10.15585/mmwr.mm6505e2.

Babaliche P, Doshi D. Catching Dengue Early: Clinical Features and Laboratory Markers of Dengue Virus Infection. J Assoc Physicians India. 2015 May;63(5):38-41.

Wahala WM, Silva AM. The human antibody response to dengue virus infection. Viruses. 2011 Dec;3(12):2374-95. doi: 10.3390/v3122374. Epub 2011 Nov 25.

Gibney KB, Edupuganti S, Panella AJ, Kosoy OI, Delorey MJ, Lanciotti RS, Mulligan MJ, Fischer M, Staples JE. Detection of anti-yellow fever virus immunoglobulin m antibodies at 3-4 years following yellow fever vaccination. Am J Trop Med Hyg. 2012 Dec;87(6):1112-5. doi: 10.4269/ajtmh.2012.12-0182. Epub 2012 Oct 29.

Roehrig JT, Nash D, Maldin B, Labowitz A, Martin DA, Lanciotti RS, Campbell GL. Persistence of virus-reactive serum immunoglobulin m antibody in confirmed west nile virus encephalitis cases. Emerg Infect Dis. 2003 Mar;9(3):376-9. doi: 10.3201/eid0903.020531.

http://www.salud.gov.pr/Estadisticas-Registros-y-Publicaciones/Informes %20Arbovirales/Reporte%20ArboV%20semana%204-2016.pdf

Chervenak FA, Jeanty P, Cantraine F, Chitkara U, Venus I, Berkowitz RL, Hobbins JC. The diagnosis of fetal microcephaly. Am J Obstet Gynecol. 1984 Jul 1;149(5):512-7. doi: 10.1016/0002-9378(84)90027-9.

Chervenak FA, Rosenberg J, Brightman RC, Chitkara U, Jeanty P. A prospective study of the accuracy of ultrasound in predicting fetal microcephaly. Obstet Gynecol. 1987 Jun;69(6):908-10.

Kurtz AB, Wapner RJ, Rubin CS, Cole-Beuglet C, Ross RD, Goldberg BB. Ultrasound criteria for in utero diagnosis of microcephaly. J Clin Ultrasound. 1980 Feb;8(1):11-6. doi: 10.1002/jcu.1870080104.

Hutchon DJ. Fetal ultrasound biometry: 1. Head reference values. Br J Obstet Gynaecol. 1999 Aug;106(8):875-6. doi: 10.1111/j.1471-0528.1999.tb08417.x. No abstract available.

Berger I. Prenatal microcephaly: can we be more accurate? J Child Neurol. 2009 Jan;24(1):97-100. doi: 10.1177/0883073808321045.

Julie A Boom; Microcephaly in infants and children: Etiology and evaluation UpToDate http://www.uptodate.com/contents/microcephaly-in-infants-and-children- etiology-and-evaluation?source=machineLearning&search=microcephaly+in +pregnacy&selectedTitle=2~130§ionRank=3&anchor=H55603463#H55603463 Accessed on February 16, 2016

Tolmie JL, McNay M, Stephenson JB, Doyle D, Connor JM. Microcephaly: genetic counselling and antenatal diagnosis after the birth of an affected child. Am J Med Genet. 1987 Jul;27(3):583-94. doi: 10.1002/ajmg.1320270311.

Atkinson B, Hearn P, Afrough B, Lumley S, Carter D, Aarons EJ, Simpson AJ, Brooks TJ, Hewson R. Detection of Zika Virus in Semen. Emerg Infect Dis. 2016 May;22(5):940. doi: 10.3201/eid2205.160107. No abstract available.

Medscape Medical News; FDA Issues Guidance to Protect Blood Supply From Zika Virus http://www.medscape.com/viewarticle/858976? nlid=100283_3901&src=wnl_newsalrt_160216_MSCPEDIT&uac=17333MK&impID=993653&faf=1

Sarno M, Sacramento GA, Khouri R, do Rosario MS, Costa F, Archanjo G, Santos LA, Nery N Jr, Vasilakis N, Ko AI, de Almeida AR. Zika Virus Infection and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal Demise. PLoS Negl Trop Dis. 2016 Feb 25;10(2):e0004517. doi: 10.1371/journal.pntd.0004517. eCollection 2016 Feb.

Brasil P, Pereira JP Jr, Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, Rabello RS, Valderramos SG, Halai UA, Salles TS, Zin AA, Horovitz D, Daltro P, Boechat M, Raja Gabaglia C, Carvalho de Sequeira P, Pilotto JH, Medialdea-Carrera R, Cotrim da Cunha D, Abreu de Carvalho LM, Pone M, Machado Siqueira A, Calvet GA, Rodrigues Baiao AE, Neves ES, Nassar de Carvalho PR, Hasue RH, Marschik PB, Einspieler C, Janzen C, Cherry JD, Bispo de Filippis AM, Nielsen-Saines K. Zika Virus Infection in Pregnant Women in Rio de Janeiro. N Engl J Med. 2016 Dec 15;375(24):2321-2334. doi: 10.1056/NEJMoa1602412. Epub 2016 Mar 4.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lebov JF, Arias JF, Balmaseda A, Britt W, Cordero JF, Galvao LA, Garces AL, Hambidge KM, Harris E, Ko A, Krebs N, Marques ETA, Martinez AM, McClure E, Miranda-Filho DB, Moreira MEL, Mussi-Pinhata MM, Ochoa TJ, Osorio JE, Scalabrin DMF, Schultz-Cherry S, Seage GR 3rd, Stolka K, Ugarte-Gil CA, Vega CMV, Welton M, Ximenes R, Zorrilla C. International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol. BMC Pregnancy Childbirth. 2019 Aug 7;19(1):282. doi: 10.1186/s12884-019-2430-4. Erratum In: BMC Pregnancy Childbirth. 2019 Nov 19;19(1):423.

• Responsible Party: RTI International
• ClinicalTrials.gov Identifier: NCT02856984
• Other Study ID Numbers: GN ZIKA
• First Posted: August 5, 2016
• Last Update Posted: August 19, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: de-identified participant data will be entered into the National Institute of Child Health and Human Development (NICHD) Data and Specimen Hub (N-DASH) system.
• Time Frame: IPD Sharing Time Frame: March 2022

Keywords provided by RTI International:

Pregnancy; Infant

Additional relevant MeSH terms:

Virus Diseases; Zika Virus Infection; Disease; Infections; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Pathologic Processes