• View in gallery
    Figure 1.

    Number (n) of suspected cases of ZIKV infections reported in the Tegucigalpa metropolitan area (Región Sanitaria Metropolitana del Distrito Central), January–December 2016 (epidemiological weeks 1–52).5 The Zika in Pregnancy in Honduras (ZIPH) study started on week 28. Crosses (+) denote Trioplex rRT-PCR assays positive for ZIKV among ZIPH participants. Crosses in a dotted line box denote both rRT-PCR assay and head circumference more than three SDs below the mean. rRT-PCR = real-time reverse transcriptase–PCR; ZIKV = Zika virus.

  • 1.

    Krauer F, Riesen M, Reveiz L, Oladapo OT, Martínez-Vega R, Porgo TV, Haefliger A, Broutet NJ, Low N, Group WZCW, 2017. Zika virus infection as a cause of congenital brain abnormalities and guillain-Barré syndrome: systematic review. PLoS Med 14: e1002203.

    • Search Google Scholar
    • Export Citation
  • 2.

    de Oliveira WK, de França GVA, Carmo EH, Duncan BB, de Souza Kuchenbecker R, Schmidt MI, 2017. Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: a surveillance-based analysis. Lancet 390: 861870.

    • Search Google Scholar
    • Export Citation
  • 3.

    Ospina ML et al. 2020. Zika virus disease and pregnancy outcomes in Colombia. N Engl J Med 383: 537545.

  • 4.

    Metsky HC et al. 2017. Zika virus evolution and spread in the Americas. Nature 546: 411415.

  • 5.

    Secretaría de Salud, Honduras, 2016. Boletin Epidemiologico. Tegucigalpa, Honduras: Republica de Honduras. Available at: http://www.salud.gob.hn/site/index.php/vigilancia.

    • Search Google Scholar
    • Export Citation
  • 6.

    Zhang Q et al. 2017. Spread of Zika virus in the Americas. Proc Natl Acad Sci U S A 114: E4334E4343.

  • 7.

    Zambrano LI, Sierra M, Lara B, Rodríguez-Núñez I, Medina MT, Lozada-Riascos CO, Rodríguez-Morales AJ, 2017. Estimating and mapping the incidence of dengue and chikungunya in Honduras during 2015 using Geographic Information Systems (GIS). J Infect Public Health 10: 446456.

    • Search Google Scholar
    • Export Citation
  • 8.

    Buekens P et al. 2016. Zika virus infection in pregnant women in Honduras: study protocol. Reprod Health 13: 82.

  • 9.

    Capurro H, Konichezky S, Fonseca D, Caldeyro-Barcia R, 1978. A simplified method for diagnosis of gestational age in the newborn infant. J Pediatr 93: 120122.

    • Search Google Scholar
    • Export Citation
  • 10.

    Villar J et al. (INTERGROWTH-21st) IFaNGCftsC, 2014. International standards for newborn weight, length, and head circumference by gestational age and sex: the newborn cross-sectional study of the INTERGROWTH-21st project. Lancet 384: 857868.

    • Search Google Scholar
    • Export Citation
  • 11.

    Harville EW, Buekens PM, Cafferata ML, Gilboa S, Tomasso G, Tong V, 2020. Measurement error, microcephaly prevalence and implications for Zika: an analysis of Uruguay perinatal data. Arch Dis Child 105: 428432.

    • Search Google Scholar
    • Export Citation
  • 12.

    Centers for Disease Control and Prevention, 2017. Trioplex Real-Time rT-PCR Assay: Instructions for Use. Available at: https://www.cdc.gov/zika/pdfs/trioplex-real-time-rt-pcr-assay-instructions-for-use.pdf. Accessed May 15, 2020.

    • Search Google Scholar
    • Export Citation
  • 13.

    Santiago GA et al. 2018. Performance of the Trioplex real-time RT-PCR assay for detection of Zika, dengue, and chikungunya viruses. Nat Commun 9: 1391.

    • Search Google Scholar
    • Export Citation
  • 14.

    Hospital Escuela, 2017. Semana epidemiologica 22, 28 de Mayo - 03 de Junio 2017. Tegucigalpa, Honduras: Hospital Escuela.

  • 15.

    Ward MJ et al. 2018. Zika virus and the World Health Organization criteria for determining recent infection using plaque reduction neutralization testing. Am J Trop Med Hyg 99: 780782.

    • Search Google Scholar
    • Export Citation
  • 16.

    Honein MA, 2018. Recognizing the global impact of Zika virus infection during pregnancy. N Engl J Med 378: 10551056.

  • 17.

    Reynolds MR et al. 2017. 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. MMWR Morb Mortal Wkly Rep 66: 366373.

    • Search Google Scholar
    • Export Citation
  • 18.

    Musso D, Ko AI, Baud D, 2019. Zika virus infection - after the pandemic. N Engl J Med 381: 14441457.

  • 19.

    Ximenes R, Ramsay LC, Miranda RN, Morris SK, Murphy K, Sander B, Team RLR, 2019. Health outcomes associated with Zika virus infection in humans: a systematic review of systematic reviews. BMJ Open 9: e032275.

    • Search Google Scholar
    • Export Citation
  • 20.

    Gallo LG et al. 2020. Another piece of the Zika puzzle: assessing the associated factors to microcephaly in a systematic review and meta-analysis. BMC Public Health 20: 827.

    • Search Google Scholar
    • Export Citation
Past two years Past Year Past 30 Days
Abstract Views 801 350 0
Full Text Views 280 112 21
PDF Downloads 225 114 19
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

 

Microcephaly Outcomes among Zika Virus–Infected Pregnant Women in Honduras

Jackeline AlgerDepartamento de Laboratorio Clínico, Hospital Escuela, Tegucigalpa, Honduras;
Instituto de Enfermedades Infecciosas y Parasitología Antonio Vidal, Tegucigalpa, Honduras;
Unidad de Investigación Científica, Facultad de Ciencias Médicas, Universidad Nacional Autónoma de Honduras (UNAH), Tegucigalpa, Honduras;

Search for other papers by Jackeline Alger in
Current site
Google Scholar
PubMed
Close
,
Pierre BuekensDepartment of Epidemiology, Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana;

Search for other papers by Pierre Buekens in
Current site
Google Scholar
PubMed
Close
,
Maria Luisa CafferataInstituto de Efectividad Clínica y Sanitaria, Buenos Aires, Argentina;
Unidad de Investigación Clínica y Epidemiológica, Montevideo, Uruguay;

Search for other papers by Maria Luisa Cafferata in
Current site
Google Scholar
PubMed
Close
,
Zulma AlvarezUnidad de Vigilancia de la Salud, Región Sanitaria Metropolitana del Distrito Central (RSMDC), Secretaría de Salud de Honduras, Tegucigalpa, Honduras;

Search for other papers by Zulma Alvarez in
Current site
Google Scholar
PubMed
Close
,
Mabel BerruetaInstituto de Efectividad Clínica y Sanitaria, Buenos Aires, Argentina;

Search for other papers by Mabel Berrueta in
Current site
Google Scholar
PubMed
Close
,
Harry BockDirección General, RSMDC, Secretaría de Salud de Honduras, Tegucigalpa, Honduras;

Search for other papers by Harry Bock in
Current site
Google Scholar
PubMed
Close
,
Carolina BustilloDepartamento de Ginecología y Obstetricia, Hospital Escuela, Tegucigalpa, Honduras;
Departamento de Ginecología y Obstetricia, Facultad de Ciencias Médicas, UNAH, Tegucigalpa, Honduras;

Search for other papers by Carolina Bustillo in
Current site
Google Scholar
PubMed
Close
,
Alejandra CalderónCentro de Salud Alonso Suazo, RSMDC, Secretaría de Salud de Honduras, Tegucigalpa, Honduras;

Search for other papers by Alejandra Calderón in
Current site
Google Scholar
PubMed
Close
,
Allison CallejasServicio de Neonatología, Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras;

Search for other papers by Allison Callejas in
Current site
Google Scholar
PubMed
Close
,
Mario CastilloServicio de Neonatología, Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras;

Search for other papers by Mario Castillo in
Current site
Google Scholar
PubMed
Close
,
Alvaro CigandaUnidad de Investigación Clínica y Epidemiológica, Montevideo, Uruguay;

Search for other papers by Alvaro Ciganda in
Current site
Google Scholar
PubMed
Close
,
Jenny FúnesServicio de Neonatología, Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras;
Departamento de Pediatría, Facultad de Ciencias Médicas, UNAH, Tegucigalpa, Honduras;

Search for other papers by Jenny Fúnes in
Current site
Google Scholar
PubMed
Close
,
Jorge GarcíaDepartamento de Laboratorio Clínico, Hospital Escuela, Tegucigalpa, Honduras;
Instituto de Enfermedades Infecciosas y Parasitología Antonio Vidal, Tegucigalpa, Honduras;

Search for other papers by Jorge García in
Current site
Google Scholar
PubMed
Close
,
Kimberly GarcíaCentro de Investigaciones Genéticas, Instituto de Investigaciones en Microbiología, Facultad de Ciencias, UNAH, Tegucigalpa, Honduras;

Search for other papers by Kimberly García in
Current site
Google Scholar
PubMed
Close
,
Luz GibbonsInstituto de Efectividad Clínica y Sanitaria, Buenos Aires, Argentina;

Search for other papers by Luz Gibbons in
Current site
Google Scholar
PubMed
Close
,
Suzanne M. GilboaDivision of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia;

Search for other papers by Suzanne M. Gilboa in
Current site
Google Scholar
PubMed
Close
,
Emily W. HarvilleDepartment of Epidemiology, Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana;

Search for other papers by Emily W. Harville in
Current site
Google Scholar
PubMed
Close
,
Gustavo HernándezDepartamento de Pediatría, Hospital de Especialidades San Felipe, Tegucigalpa, Honduras;

Search for other papers by Gustavo Hernández in
Current site
Google Scholar
PubMed
Close
,
Raquel LópezInstituto de Enfermedades Infecciosas y Parasitología Antonio Vidal, Tegucigalpa, Honduras;

Search for other papers by Raquel López in
Current site
Google Scholar
PubMed
Close
,
Wendy LópezDepartamento de Laboratorio Clínico, Hospital Escuela, Tegucigalpa, Honduras;
Instituto de Enfermedades Infecciosas y Parasitología Antonio Vidal, Tegucigalpa, Honduras;

Search for other papers by Wendy López in
Current site
Google Scholar
PubMed
Close
,
Ivette LorenzanaCentro de Investigaciones Genéticas, Instituto de Investigaciones en Microbiología, Facultad de Ciencias, UNAH, Tegucigalpa, Honduras;

Search for other papers by Ivette Lorenzana in
Current site
Google Scholar
PubMed
Close
,
Marco Tulio LuqueServicio de Infectología, Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras;

Search for other papers by Marco Tulio Luque in
Current site
Google Scholar
PubMed
Close
,
Carlos MaldonadoServicio de Oftalmología, Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras;

Search for other papers by Carlos Maldonado in
Current site
Google Scholar
PubMed
Close
,
Cynthia A. MooreDivision of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia;

Search for other papers by Cynthia A. Moore in
Current site
Google Scholar
PubMed
Close
,
Carlos OchoaServicio de Maternidad, Hospital de Especialidades San Felipe, Tegucigalpa, Honduras;

Search for other papers by Carlos Ochoa in
Current site
Google Scholar
PubMed
Close
,
Leda ParhamCentro de Investigaciones Genéticas, Instituto de Investigaciones en Microbiología, Facultad de Ciencias, UNAH, Tegucigalpa, Honduras;
Escuela de Microbiología, Facultad de Ciencias, UNAH, Tegucigalpa, Honduras;

Search for other papers by Leda Parham in
Current site
Google Scholar
PubMed
Close
,
Karla PastranaDepartamento de Ginecología y Obstetricia, Hospital Escuela, Tegucigalpa, Honduras;
Departamento de Ginecología y Obstetricia, Facultad de Ciencias Médicas, UNAH, Tegucigalpa, Honduras;

Search for other papers by Karla Pastrana in
Current site
Google Scholar
PubMed
Close
,
Fátima RicoDepartamento de Pediatría, Facultad de Ciencias Médicas, UNAH, Tegucigalpa, Honduras;
Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras;

Search for other papers by Fátima Rico in
Current site
Google Scholar
PubMed
Close
,
Heriberto RodríguezSub-Dirección, Hospital de Especialidades San Felipe, Tegucigalpa, Honduras;

Search for other papers by Heriberto Rodríguez in
Current site
Google Scholar
PubMed
Close
,
Candela StellaInstituto de Efectividad Clínica y Sanitaria, Buenos Aires, Argentina;

Search for other papers by Candela Stella in
Current site
Google Scholar
PubMed
Close
,
Diana ValenciaDivision of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia;

Search for other papers by Diana Valencia in
Current site
Google Scholar
PubMed
Close
,
Douglas VarelaServicio de Neurología, Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras;

Search for other papers by Douglas Varela in
Current site
Google Scholar
PubMed
Close
,
Dawn M. WessonDepartment of Tropical Medicine, Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana;

Search for other papers by Dawn M. Wesson in
Current site
Google Scholar
PubMed
Close
,
Concepción ZúnigaInstituto de Enfermedades Infecciosas y Parasitología Antonio Vidal, Tegucigalpa, Honduras;
Departamento de Vigilancia de la Salud, Hospital Escuela, Tegucigalpa, Honduras

Search for other papers by Concepción Zúniga in
Current site
Google Scholar
PubMed
Close
, and
Van T. TongDivision of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia;

Search for other papers by Van T. Tong in
Current site
Google Scholar
PubMed
Close

ABSTRACT

The impact of Zika virus (ZIKV) infection on pregnancies shows regional variation emphasizing the importance of studies in different geographical areas. We conducted a prospective study in Tegucigalpa, Honduras, recruiting 668 pregnant women between July 20, 2016, and December 31, 2016. We performed Trioplex real-time reverse transcriptase–PCR (rRT-PCR) in 357 serum samples taken at the first prenatal visit. The presence of ZIKV was confirmed in seven pregnancies (7/357, 2.0%). Nine babies (1.6%) had microcephaly (head circumference more than two SDs below the mean), including two (0.3%) with severe microcephaly (head circumference [HC] more than three SDs below the mean). The mothers of both babies with severe microcephaly had evidence of ZIKV infection. A positive ZIKV Trioplex rRT-PCR was associated with a 33.3% (95% CI: 4.3–77.7%) risk of HC more than three SDs below the mean.

The World Health Organization (WHO) Zika Causality Working Group’s systematic review found sufficient evidence to conclude that Zika virus (ZIKV) is a cause of congenital abnormalities but with noted differences between countries.1 The increase in the number of cases of microcephaly potentially associated with ZIKV was large in Northeast Brazil in 2015. It was lower in other regions of Brazil and in other countries.2,3 The reason for these variations is unknown and emphasizes the importance of studying the impact of ZIKV infection in different geographical areas, including Central America. Phylogenetic evidence suggests that Zika virus (ZIKV) arrived in Honduras in 2015,4 but the epidemic occurred in 2016, when a total of 32,132 suspected cases of ZIKV infections were recorded, including 10,386 cases from the Tegucigalpa metropolitan area (Región Metropolitana del Distrito Central).5 At the national level, the number of reported cases was the highest at the beginning of 2016, reflecting an initial concentration of ZIKV infections in the San Pedro Sula area (Cortes Department, Atlantic coast).4,6 In the Tegucigalpa metropolitan area, the number of reported cases was at its height in mid-2016 (Figure 1),5 reflecting the season with the highest risk of mosquito-borne disease transmission, as illustrated by previous studies on circulation of dengue virus (DENV) and chikungunya virus (CHIKV).7

Figure 1.
Figure 1.

Number (n) of suspected cases of ZIKV infections reported in the Tegucigalpa metropolitan area (Región Sanitaria Metropolitana del Distrito Central), January–December 2016 (epidemiological weeks 1–52).5 The Zika in Pregnancy in Honduras (ZIPH) study started on week 28. Crosses (+) denote Trioplex rRT-PCR assays positive for ZIKV among ZIPH participants. Crosses in a dotted line box denote both rRT-PCR assay and head circumference more than three SDs below the mean. rRT-PCR = real-time reverse transcriptase–PCR; ZIKV = Zika virus.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 5; 10.4269/ajtmh.20-1483

We conducted a prospective pregnancy cohort study in Tegucigalpa, Honduras: the Zika in Pregnancy in Honduras (ZIPH) study to investigate the impact of congenital ZIKV infection. The ZIPH protocol was previously published.8 We enrolled pregnant women at their first prenatal visit and followed up them through delivery. At the time of enrollment, women were interviewed to collect sociodemographic data. Data about ZIKV symptoms during pregnancy were collected at the first visit and at delivery. Infant head circumference (HC) at birth and gestational age estimated by last menstrual period, prenatal ultrasound, clinical examination, or Capurro scores9 were used to classify microcephaly. Using the INTERGROWTH-21st standards for gender and gestational age, microcephaly at birth was defined as HC more than two SDs below the mean; severe microcephaly was defined as HC more than three SDs below the mean.10,11 Clinical data, such as neuroimaging, were abstracted from available medical records for those infants born to women with positive ZIKV by real-time reverse transcriptase–PCR (rRT-PCR) results. Enrollment into the cohort started in July 2016 and continues. The current analysis is among pregnant women enrolled until December 31, 2016, during the end of the ZIKV outbreak in Honduras.

Venous maternal blood was collected once as soon as possible after enrollment at the first prenatal visit, regardless of symptoms. Blood samples were initially frozen at or below −20°C and later at or below −80°C until testing. We conducted molecular testing for ZIKV, DENV, and CHIKV on maternal serum samples using the Trioplex rRT-PCR assay, which detects RNA from all three viruses simultaneously, following CDC protocols.12,13 Consent forms include an opt-out provision that otherwise allows participating study institutions to store blood specimens for up to 10 years. No laboratory testing was performed on infants.

We computed the frequency of ZIKV infection at the first prenatal visit among enrolled women (“exposed women”). We also computed the frequency of HC more than two SDs and more than three SDs below the mean in infants. We calculated the risk for microcephaly in exposed and unexposed infants with the corresponding Fisher exact 95% CIs. We used R version 4.0.0 for data analysis. This study was approved by the Tulane University and the Faculty of Medical Sciences, Universidad Nacional Autónoma de Honduras institutional review boards.

All 705 women attending prenatal care at Alonso Suazo Health Center between July 20, 2016 and December 31, 2016 were screened for enrollment; 668 provided written informed consent and were recruited from the center (Supplemental Material, Figure S1). The first prenatal visit occurred before 14 weeks of gestation in 62.8% of women (Table 1). Seventeen women reported symptoms compatible with ZIKV infection during pregnancy. We collected information from medical records of 644 (96.4%) women at the end of their pregnancy, including 599 live births, 36 pregnancy losses, and nine stillbirths. The gestational age at birth was based on the last menstrual period (82.6%, 516/625), ultrasound (14.2%, 89/625), clinical examination (3.7%, 23/625), or Capurro score (0.2%, 1/625). The proportion of preterm deliveries (< 37 weeks) was 15.5%; 11.5% of pregnancies resulted in a low-birthweight newborn (< 2,500 g) (Table 1). Nine babies (1.6%) had microcephaly, including two (0.3%) with severe microcephaly (Table 2). Figure 1 shows that the mothers of babies with severe microcephaly were recruited in early August 2016, at the very beginning of the recruitment period.

Table 1

Maternal and neonatal characteristics among women with and without serum samples tested by Trioplex rRT-PCR assay ZIPH study, Honduras, 2016

All women (N = 667)rRT-PCR performed (N = 357)No rRT-PCR performed (N = 310)
n/N*%n/N%n/N%
Maternal age-group (years)
 12–19198/66729.791/35725.5107/31034.5
 20–34404/66760.6233/35765.3171/31055.2
 35 or older65/6679.733/3579.232/31010.3
Years of education and range 96–1296–1296–11
Gestational age at the first visit (weeks)
 Between one and 13374/59662.8198/32261.5176/27464.2
 Between 14 and 27176/59629.597/32230.179/27428.8
 28 or older46/5967.727/3228.419/2746.9
Symptoms during pregnancy
 Skin rash12/6441.97/3532.05/2911.7
 Fever15/6442.38/3532.37/2912.4
 Arthralgia11/6441.75/3531.46/2912.1
 Arthritis3/6440.52/3530.61/2910.3
 Conjunctivitis5/6440.82/3530.63/2911.0
 None626/64497.2343/35397.2283/29197.3
Preterm birth (less than 37 weeks)97/62515.554/34815.543/27715.5
Low birthweight (< 2,500 g)68/59211.530/3299.138/26314.4
Very low birthweight (< 1,500 g)11/5921.93/3290.98/2633.0
Microcephaly (HC < 2 SD)9/5781.66/3231.93/2551.2
Severe microcephaly (HC < 3 SD)2/5780.32/3230.60/2550.0
Newborn status
 Alive599/64493.0332/35394.1267/29191.8
 Still birth9/6441.44/3531.15/2911.7
 Pregnancy loss36/6445.617/3534.819/2916.5

HC= head circumference; rRT-PCR = real-time reverse transcriptase–PCR.

The denominators presented reflect the number of participants with information in the ZIPH study.

Median [interquartile range].

Table 2

Zika virus (ZIKV) rRT-PCR results and microcephaly, ZIPH study, Honduras, 2016

ZIKV +ZIKV −No rRT-PCR performed
Head circumferencen/N%n/N%n/N%Total
Microcephaly2/633.34/3171.33/2551.29
Severe2/21000/40/3
No microcephaly4/666.6313/31798.7252/25598.8569
Not measured1335589
Total7350310667

rRT-PCR = real-time reverse transcriptase–PCR; ZIKV = Zika virus.

Data collected from medical records suggested that the two babies with severe microcephaly had Zika-associated birth defects (see Supplemental Material). The first newborn had a malformed skull with a narrow forehead and a cerebral tomography showing ventriculomegaly, agenesis of the corpus callosum, and multiple calcifications. The second newborn had a malformed skull with a prominent occiput, and a cerebral tomography with ventriculomegaly and multiple calcifications.

A blood sample was taken at the first prenatal visit in 667 recruited women (Supplemental Figure S1). Almost half of the participants (45.8%, 306/667) did not consent to their blood samples being stored long term to permit testing when resources would potentially become available. We performed rRT-PCR among 357 women who consented to the long-term storage of their blood samples (Supplemental Figure S1). Table 1 shows that the characteristics of the women with and without consent to store samples were similar. Of those who consented, seven (7/357, 2.0%) were ZIKV positive (Table 2). Two of the women with ZIKV-positive results had symptoms during pregnancy (Supplemental Material, Table S1). Figure 1 shows that four of the ZIKV-positive mothers were recruited at the very beginning of the study. Both mothers of babies with severe microcephaly were ZIKV positive. No other newborn born to mothers with positive ZIKV had microcephaly (Table 2). A positive ZIKV test at the first prenatal visit (n = 6) was associated with a 33.3% (95% CI: 4.3–77.7) risk of severe microcephaly, whereas the risk was 0 (95% CI: 0–1.2) in 317 unexposed.

Our results show an association between confirmed ZIKV infection in the first half of pregnancy and severe microcephaly. Both cases of severe microcephaly were recruited at the beginning of the study, close to the estimated peak of the epidemic in Honduras (Figure 1), and were born in January and February 2017. This is consistent with monthly reports from the largest hospital in Tegucigalpa showing an increase of cases of microcephaly from July 2016 to February 2017, with a peak of 11 cases per month in December 2016 and January 2017, compared with one case or less per month before July 2016.14 The two cases of severe microcephaly in the current study were not sufficient to substantially increase the overall rates of microcephaly. We observed similar lower than expected rates of microcephaly in Uruguay during 2010–2015.11

The official data on reported ZIKV cases (Figure 1) are based on suspected cases, often not confirmed by laboratory analyses. Both over- and underreporting are possible, but the shape of the time distribution is most likely accurate. We previously published plaque reduction neutralization test results confirming that the ZIPH study population was exposed to ZIKV.15

In the United States, the risk of ZIKV-associated birth defects was 15%, with laboratory-confirmed ZIKV infection during the first trimester; however, the case definition was broader and included brain abnormalities identified with neuroimaging and eye abnormalities based on ophthalmological examination.16,17 The risk of microcephaly among infected women is estimated to be 4–6% globally.18 A recent systematic review found high heterogeneity among studies, with microcephaly risk among infected women varying from 0.9% to 30%.19 In our study, 33.3% (95% CI: 4.3–77.7) of women with a positive ZIKV test at the first prenatal visit delivered an infant with microcephaly. Both cases of severe microcephaly were born to mothers whose blood was drawn during the first half of their pregnancies (13 and 16 weeks of gestation), in agreement with the literature showing that the risk of Zika-associated birth defects is higher when the mother is infected by ZIKV at the beginning of pregnancy.20 Only one of the two mothers was symptomatic, which is consistent with the literature suggesting that risk is similar for ZIKV infection regardless of the presence of symptoms.19

Our study was initially designed as a case–cohort study to limit laboratory analyses,8 but additional funds allowed us to test women recruited in 2016. Samples from women who did not agree for their blood sample to be stored for more than 1 year after delivery could not be tested, but characteristics of women with and without rRT-PCR were similar. Another limitation of the ZIPH study is that we only collected a blood sample at the first prenatal visit. Despite the limitations of the study and the small numbers, the simplified protocol of the ZIPH study allowed us to initiate the study quickly, at the peak of the ZIKV epidemic in Tegucigalpa. We conclude that ZIKV infection in early pregnancy is associated with severe microcephaly in Honduras as observed in other regions of the Americas.

Supplemental information, table, and figure

ACKNOWLEDGMENTS

We thank Karla Rivera and Renato Valenzuela for their administrative support. We thank Andrea Meyer for editing this manuscript.

REFERENCES

  • 1.

    Krauer F, Riesen M, Reveiz L, Oladapo OT, Martínez-Vega R, Porgo TV, Haefliger A, Broutet NJ, Low N, Group WZCW, 2017. Zika virus infection as a cause of congenital brain abnormalities and guillain-Barré syndrome: systematic review. PLoS Med 14: e1002203.

    • Search Google Scholar
    • Export Citation
  • 2.

    de Oliveira WK, de França GVA, Carmo EH, Duncan BB, de Souza Kuchenbecker R, Schmidt MI, 2017. Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: a surveillance-based analysis. Lancet 390: 861870.

    • Search Google Scholar
    • Export Citation
  • 3.

    Ospina ML et al. 2020. Zika virus disease and pregnancy outcomes in Colombia. N Engl J Med 383: 537545.

  • 4.

    Metsky HC et al. 2017. Zika virus evolution and spread in the Americas. Nature 546: 411415.

  • 5.

    Secretaría de Salud, Honduras, 2016. Boletin Epidemiologico. Tegucigalpa, Honduras: Republica de Honduras. Available at: http://www.salud.gob.hn/site/index.php/vigilancia.

    • Search Google Scholar
    • Export Citation
  • 6.

    Zhang Q et al. 2017. Spread of Zika virus in the Americas. Proc Natl Acad Sci U S A 114: E4334E4343.

  • 7.

    Zambrano LI, Sierra M, Lara B, Rodríguez-Núñez I, Medina MT, Lozada-Riascos CO, Rodríguez-Morales AJ, 2017. Estimating and mapping the incidence of dengue and chikungunya in Honduras during 2015 using Geographic Information Systems (GIS). J Infect Public Health 10: 446456.

    • Search Google Scholar
    • Export Citation
  • 8.

    Buekens P et al. 2016. Zika virus infection in pregnant women in Honduras: study protocol. Reprod Health 13: 82.

  • 9.

    Capurro H, Konichezky S, Fonseca D, Caldeyro-Barcia R, 1978. A simplified method for diagnosis of gestational age in the newborn infant. J Pediatr 93: 120122.

    • Search Google Scholar
    • Export Citation
  • 10.

    Villar J et al. (INTERGROWTH-21st) IFaNGCftsC, 2014. International standards for newborn weight, length, and head circumference by gestational age and sex: the newborn cross-sectional study of the INTERGROWTH-21st project. Lancet 384: 857868.

    • Search Google Scholar
    • Export Citation
  • 11.

    Harville EW, Buekens PM, Cafferata ML, Gilboa S, Tomasso G, Tong V, 2020. Measurement error, microcephaly prevalence and implications for Zika: an analysis of Uruguay perinatal data. Arch Dis Child 105: 428432.

    • Search Google Scholar
    • Export Citation
  • 12.

    Centers for Disease Control and Prevention, 2017. Trioplex Real-Time rT-PCR Assay: Instructions for Use. Available at: https://www.cdc.gov/zika/pdfs/trioplex-real-time-rt-pcr-assay-instructions-for-use.pdf. Accessed May 15, 2020.

    • Search Google Scholar
    • Export Citation
  • 13.

    Santiago GA et al. 2018. Performance of the Trioplex real-time RT-PCR assay for detection of Zika, dengue, and chikungunya viruses. Nat Commun 9: 1391.

    • Search Google Scholar
    • Export Citation
  • 14.

    Hospital Escuela, 2017. Semana epidemiologica 22, 28 de Mayo - 03 de Junio 2017. Tegucigalpa, Honduras: Hospital Escuela.

  • 15.

    Ward MJ et al. 2018. Zika virus and the World Health Organization criteria for determining recent infection using plaque reduction neutralization testing. Am J Trop Med Hyg 99: 780782.

    • Search Google Scholar
    • Export Citation
  • 16.

    Honein MA, 2018. Recognizing the global impact of Zika virus infection during pregnancy. N Engl J Med 378: 10551056.

  • 17.

    Reynolds MR et al. 2017. 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. MMWR Morb Mortal Wkly Rep 66: 366373.

    • Search Google Scholar
    • Export Citation
  • 18.

    Musso D, Ko AI, Baud D, 2019. Zika virus infection - after the pandemic. N Engl J Med 381: 14441457.

  • 19.

    Ximenes R, Ramsay LC, Miranda RN, Morris SK, Murphy K, Sander B, Team RLR, 2019. Health outcomes associated with Zika virus infection in humans: a systematic review of systematic reviews. BMJ Open 9: e032275.

    • Search Google Scholar
    • Export Citation
  • 20.

    Gallo LG et al. 2020. Another piece of the Zika puzzle: assessing the associated factors to microcephaly in a systematic review and meta-analysis. BMC Public Health 20: 827.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Pierre Buekens, W. H. Watkins Professor of Epidemiology School of Public Health and Tropical Medicine, Tulane University, 1440 Canal St., Suite 2001, New Orleans, LA 70112. E-mail: pbuekens@tulane.edu

CDC Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.

Financial support: The Zika in Pregnancy in Honduras (ZIPH) study is partially funded by Vysnova Partners SC-2018-3045-TU.

Authors’ addresses: Jackeline Alger, Jorge García, and Wendy López, Departamento de Laboratorio Clínico, Hospital Escuela Universitario, Tegucigalpa, Honduras, and Instituto de Enfermedades Infecciosas y Parasitología Antonio Vidal (IAV), Tegucigalpa, Honduras, E-mails: jackelinealger@gmail.com, jalgar62_84@yahoo.com.ar and wlopez36@hotmail.com. Pierre Buekens, Emily W. Harville, and Dawn M. Wesson, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, E-mails: pbuekens@tulane.edu, eharvill@tulane.edu, and wesson@tulane.edu. Maria Luisa Cafferata, Mabel Berrueta, Luz Gibbons, and Candela Stella, Instituto de Efectividad Clínica y Sanitaria (IECS), Buenos Aires, Argentina, E-mails: marialuisa.cafferata@gmail.com, mberrueta@iecs.org.ar, lgibbons@iecs.org.ar, and cstella@iecs.org.ar. Zulma Alvarez and Harry Bock, Región Sanitaria Metropolitana del Distrito Central, Secretaría de Salud de Honduras, Tegucigalpa, Honduras, E-mails: zulmahen@yahoo.com and hbockme@hotmail.com. Carolina Bustillo and Karla Pastrana, Departamento de Ginecología y Obstetricia, Facultad de Ciencias Médicas, UNAH, Tegucigalpa, Honduras, E-mails: mcbu1502@yahoo.com and kpastrana_2000@yahoo.com.mx. Alejandra Calderón, Centro de Salud Alonso Suazo, Región Sanitaria Metropolitana del Distrito Central, Secretaría de Salud de Honduras, Tegucigalpa, Honduras, E-mail: lilianalecalderon@gmail.com. Allison Callejas, Mario Castillo, and Jenny Fúnes, Servicio de Neonatología, Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras, E-mails: amariecs1981@gmail.com, mariocastillo26@yahoo.com, and jennylagosfunes@yahoo.com. Alvaro Ciganda, Unidad de Investigación Clínica y Epidemiológica, Montevideo, Uruguay, E-mail: aciganda@gmail.com. Kimberly García, Ivette Lorenzana, and Leda Parham, Facultad de Ciencias, UNAH, Tegucigalpa, Honduras, E-mails: kimfa_2010@hotmail.com, ivettelorenzana@yahoo.com, and lparham29@hotmail.com. Suzanne M. Gilboa, Cynthia A. Moore, Diana Valencia, and Van T. Tong, Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, E-mails: suz0@cdc.gov, cam0@cdc.gov, ile9@cdc.gov, and vct2@cdc.gov. Gustavo Hernández, Carlos Ochoa, Heriberto Rodríguez, Hospital de Especialidades San Felipe, Tegucigalpa, Honduras, E-mails: ghernandezbustillo@yahoo.es, caof@email.com, and mmfhrg@gmail.com. Raquel López, Instituto de Enfermedades Infecciosas y Parasitología Antonio Vidal, Tegucigalpa, Honduras, E-mail: raquelbonilla_86@hotmail.com. Marco Tulio Luque, Carlos Maldonado, Fátima Rico, Douglas Varela, Departamento de Pediatría, Hospital Escuela, Tegucigalpa, Honduras, E-mails: mtluque@yahoo.com, cmcolegiaciones@gmail.com, ricourrea7@gmail.com, and douglasvarela2068@gmail.com. Concepción Zúniga, Departamento de Vigilancia de la Salud, Hospital Escuela, Tegucigalpa, Honduras, E-mail: concepcionzuniga@gmail.com.

These authors contributed equally to this work.

Save