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Is Pregnancy Associated with Severe Dengue? A Review
of Data from the Rio de Janeiro Surveillance Information
System
Carolina Romero Machado
1
, Elizabeth Stankiewicz Machado
2
*, Roger Denis Rohloff
3
, Marina Azevedo
4
,
Dayse Pereira Campos
1
, Robson Bruniera de Oliveira
1
, Patrı
´cia Brasil
1
1Instituto de Pesquisa Clı
´nica Evandro Chagas, Fiocruz, Rio de Janeiro, Rio de Janeiro, Brasil, 2Servic¸o de Doenc¸ as Infecciosas e Parasita
´rias, Hospital Universita
´rio
Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil, 3Maternidade Municipal Fernando Magalha
˜es, Rio de Janeiro, Rio de Janeiro, Brasil,
4Secretaria Municipal de Sau
´de e Defesa Civil do Rio de Janeiro SMSDC-RJ, Rio de Janeiro, Rio de Janeiro, Brasil
Abstract
Background:
Dengue is a reportable disease in Brazil; however, pregnancy has been included in the application form of the
Brazilian notification information system only after 2006. To estimate the severity of maternal dengue infection, the
available data that were compiled from January 2007 to December 2008 by the official surveillance information system of
the city of Rio de Janeiro were reviewed.
Methods and Principal Findings:
During the study period, 151,604 cases of suspected dengue infection were reported. Five
hundred sixty-one women in their reproductive age (15–49 years) presented with dengue infection; 99 (18.1%) pregnant
and 447 (81.9%) non-pregnant women were analyzed. Dengue cases were categorized using the 1997 WHO classification
system, and DHF/DSS were considered severe disease. The Mann-Whitney test was used to compare maternal age,
according to gestational period, and severity of disease. A chi-square test was utilized to evaluate the differences in the
proportion of dengue severity between pregnant and non-pregnant women. Univariate analysis was performed to compare
outcome variables (severe dengue and non-severe dengue) and explanatory variables (pregnancy, gestational age and
trimester) using the Wald test. A multivariate analysis was performed to assess the independence of statistically significant
variables in the univariate analysis. A p-value,0.05 was considered statistically significant.
A higher percentage of severe dengue infection among pregnant women was found, p= 0.0001. Final analysis
demonstrated that pregnant women are 3.4 times more prone to developing severe dengue (OR: 3.38; CI: 2.10–5.42).
Mortality among pregnant women was superior to non-pregnant women.
Conclusion:
Pregnant women have an increased risk of developing severe dengue infection and dying of dengue.
Citation: Machado CR, Machado ES, Rohloff RD, Azevedo M, Campos DP, et al. (2013) Is Pregnancy Associated with Severe Dengue? A Review of Data from the
Rio de Janeiro Surveillance Information System. PLoS Negl Trop Dis 7(5): e2217. doi:10.1371/journal.pntd.0002217
Editor: Scott B. Halstead, Pediatric Dengue Vaccine Initiative, United States of America
Received January 4, 2012; Accepted April 1, 2013; Published May 9, 2013
Copyright: ß2013 Machado et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have indicated that no funding was received for this work.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: emachado@infolink.com.br
Introduction
Since the reintroduction of DENV-1 in 1986 in RJ, dengue
has become a major public health problem in Brazil [1]. The
occurrence of dengue fever (DF) and dengue hemorrhagic fever
(DHF) has increased over the past several years in Brazil, in
part due to the rapid spread and simultaneous circulation of
the DENV-1, DENV-2, DENV-3 [1]. In 2008, over 600,000
cases of DF and 4,455 cases of DHF were reported in Brazil,
with 40% and 42%, respectively, occurring in the state of RJ
[2,3].
A surveillance information system of reportable diseases,
SINAN, was implemented in Brazil in the early 1980s [4], and
since then, dengue has been a compulsory reportable disease.
However, pregnancy was a reportable item on the form only after
2006.
Globally, there are increasing reports of dengue during
adulthood, increasing the risk for dengue during pregnancy. In
the literature only approximately 400 cases of dengue during
pregnancy have been reported, primarily describing the maternal
and fetal outcomes [5,6]. If diseases such as malaria and cholera
are more severe during pregnancy, would dengue also be more
severe? During the 2007/2008 epidemic in the city of RJ, the
highest rate of laboratory-positive dengue samples was among
those in the age group under 15 years, followed by those 15–29
years; 99% of all births during this period occurred in mothers
aged 15–49 years [7].
To estimate the severity of maternal dengue, the available data
provided by SINAN related to the epidemic period of January 1,
2007, through December 31, 2008, in the city of RJ, were
reviewed. Laboratory-confirmed dengue cases in reproductive-age
women (15–49 years) were included. Mortality and severity of the
PLOS Neglected Tropical Diseases | www.plosntds.org 1 May 2013 | Volume 7 | Issue 5 | e2217
disease were compared between pregnant and non-pregnant
women.
Methods
Data source (SINAN form)
A suspected dengue case is routinely reported to SINAN within
24 hours of attendance in a healthcare unit, using a standardized
form [8]. When the laboratory results are available, the form is
completed by a health staff member who reviews the chart
information and adds the final dengue classification, usually after a
period of no more than 3 months. Suspected cases are reported
from all healthcare facilities in RJ.
The SINAN form includes information on basic demogra-
phy, laboratory data, hospitalization and outcomes (death or
cure). Dengue cases are classified according to the WHO
1997 [9], adapted by the Brazilian Ministry of Health to
include the category of dengue with complications [10] for the
cases that do not fulfill all three criteria for DHF. Laboratory
confirmed cases were considered when either virus isolation,
PCR testing, paired IgM or IgG testing or single IgM test was
positive.
Pregnancy is categorized in the SINAN form according to
trimester: 1
st
trimester (up to 14 weeks of gestation), 2
nd
trimester
(14–28 weeks), 3
rd
trimester (after 28 weeks) or unidentified
gestational age.
Study population
Eligibility criteria. childbearing-age women with complete-
ness information about pregnancy, dengue classification and
laboratory confirmation.
During 2007–2008, of 151,604 suspected dengue cases reported
to SINAN in RJ, 76,990 occurred in women. Those with age less
than 15 years or over 49 years (n = 17,985) were excluded,
resulting in 50,005 suspected dengue cases in reproductive-age
women. Laboratory dengue confirmation corresponded to 3,972
cases. Of these, 546 were eligible.
The mean population of reproductive-age women in the city of
RJ in the period was 1,700,036: 83,332 pregnant and 1,616,704
non-pregnant women [7].
To estimate dengue-mortality and fatality rates, it was assumed
the ratio of 5% [7] pregnancy among childbearing-age women,
corresponding to 199 pregnant and 3773 non-pregnant infected
women.
Deaths due to dengue occurred in 3 pregnant women and 28 in
non-pregnant women.
Dengue classification
Patients were categorized according to the WHO 1997
classification system as DF, DHF or DSS [10]. Dengue
classification of patients (n = 117) categorized in the SINAN form
as ‘dengue with complications’ were reviewed. If patients had
evidence of plasma leakage they were categorized as having DHF/
DSS and thus considered as severe cases. Otherwise, patients were
categorized as having DF.
Statistical analysis
The Mann-Whitney Utest was used to test the difference
between the mean age of pregnant and non-pregnant women and
the difference between the mean age of pregnant women by
dengue classification (DF and DHF/DSS).
A chi-square test was used to evaluate the differences in the
proportion of dengue severity between pregnant and non-pregnant
women. A p-value of ,0.05 was considered significant in all
statistical tests.
A univariate analysis was performed using DHF/DSS (depen-
dent variable) and pregnancy, maternal age (as a continuous
variable) and trimester (independent variables) using the Wald test.
Multiple logistic regression analysis was used to determine whether
statistically significant variables were independently associated
with dengue severity. Variables with a p-value,0.05 in the
univariate analysis were included in the multivariate analysis.
Finally, the residuals of the fitted model were analyzed. With this
modeling, the odds ratio and their respective confidence intervals
(95%) were obtained. All statistical analyses of data were
performed using Rsoftware, version 2.11.1.
Ethics statement
Our study was reviewed and approved by the Ethical
Committee of the Municipal Secretary of the City of Rio de
Janeiro: ComiteˆdeE
´tica em Pesquisa da Secretaria Municipal de
Sau´de e Defesa Civil. Protocolo de pesquisa: 51/08. CAAE:
0122.1.314.000-08 e 0130.1.314.000-08. Inform consent was not
obtained because the data were analyzed anonymously.
Results
The incidence of laboratory confirmed dengue among women
in reproductive age was 234/100,000 inhabitants/2y, with similar
rates between pregnant (238/100,000) and non-pregnant women
(233/100,000). Mortality of dengue was 3,6/100,000 inhabitants/
2y among pregnant women and 1,7/100,000 inhabitants/2y
among non-pregnant women. Case fatality rate was 7,4 and 1,5%
respectively.
Data on 546 eligible reproductive-age women who had
confirmed cases of dengue were analyzed: 99 (18.1%) were
pregnant and 447 (81.9%) were not (table 1). The mean (6
standard deviation) maternal age was significantly different:
26.368.5 years in pregnant women compared with 31.5610.7
years in non-pregnant women (p,0.05). No significant difference
Author Summary
Dengue represents a major worldwide public health
problem. According to the WHO, up to 50 million dengue
infections occur each year. The occurrence of dengue fever
and dengue hemorrhagic fever has increased in Brazil, in
part due to the simultaneous circulation of DENV-1, DENV-
2 and DENV-3. Although a primary infection with one
serotype confers a partial or transient immunity against
other serotypes, any subsequent infections harbor the risk
of increased morbidity/mortality. Several case reports have
been published regarding maternal and fetal outcomes
from dengue infection, but it is still inconclusive if
pregnancy is associated with severity. To estimate the
severity of maternal dengue infection, available data that
were compiled from 2007 to 2008 by the official
surveillance information system of the city of Rio de
Janeiro were reviewed. The cases of dengue were analyzed
using the 1997 WHO classification. Pregnant women were
3.4 times more prone to developing severe dengue than
non-pregnant women. Mortality among pregnant women
was superior to non-pregnant women. The increased risk
of severe outcomes in pregnant women merits further
attention to effective public health and medical interven-
tions that will aid in avoiding morbidity/fatalities within
this population.
Dengue Infection Severity among Pregnant Women
PLOS Neglected Tropical Diseases | www.plosntds.org 2 May 2013 | Volume 7 | Issue 5 | e2217
was observed in the mean age between pregnant women with
DHF/DSS (25.568.2) and DF (26.968.5).
Most cases were classified as DF (n = 417, 76.4%), 123 as DHF
(22.5%) and 6 as DSS (1.1%). A higher proportion of pregnant
women than non-pregnant women had DHF/DSS (table 1).
Hospitalization information available for 186 (34.1%) patients
occurred in 61 (34.1%) pregnant women, and in 118 (65.9%) non-
pregnant women. The proportion of severe dengue among
hospitalized women was similar: 73.8% and 66.9% for pregnant
and non-pregnant women, respectively.
Information on death was available for 395 (72.3%) of the
eligible cases: three pregnant and five non-pregnant women died
(table 1). Shock syndrome (n = 3) and cavity effusion (n =2) were
associated with deaths. The cause of death was unknown in three
patients.
A higher prevalence of DHF/DSS that increased with gestation
age was observed (table 2). Pregnant women were 3.4 times more
likely to have DHF/DSS, primarily in the last trimester; OR 3.38;
CI 2.1–5.42 (table 3).
Discussion
This study suggests that dengue during pregnancy can increase
maternal mortality, as previously reported [11]. It also suggests
that pregnancy is associated with DHF/DSS and that the
susceptibility to severe disease increases with pregnancy age.
Severe dengue has been associated with maternal deaths, with
fatality rates ranging from 2.9%–22% [5–6,11–13]. The maternal
dengue fatality in this study was 7.4%. The differences in dengue
fatality in pregnant women likely result from differences in the
designs and in the heterogeneity of the studies sample sizes.
Additionally, it may represent different regional management of
dengue in pregnant women.
More than half of pregnant women were hospitalized and it
was twice the rate of hospitalization for non-pregnant women,
since it was a recommendation of Rio de Janeiro’s healthcare
authorities to prevent dengue complications in this group.
Moreover, the proportion of DHF could still be underestimated
as the identification of plasma leakage syndrome through the
hemoconcentration or hypoproteinemia may be compromised
from the seventh to the 32rd week of gestation, by the
physiological increase of intravascular volume of this period
[14].
The reasons for the association of DHF/DSS with pregnancy
were not assessed in this study. The amount of vascular leakage
during early versus late pregnancy may have different effects on
the clinical presentation and on the perceived severity level. The
higher risk for developing severe disease in the 2
nd
and 3
rd
trimesters should be confirmed by prospective studies as the
selection bias related to admission because of risk of preterm
delivery cannot be excluded.
The non-laboratory confirmed dengue cases were not analyzed
to avoid a detection bias, and the confusion of dengue with
pregnancy complications, such as HELLP syndrome.
The findings of the study are based on a retrospective review of
routinely collected data, with laboratory confirmed dengue, which
Table 1. Mean age, dengue classification, hospitalization and
death in pregnant and non-pregnant women of reproductive
age.
Women of reproductive age
Pregnant (N = 99) Non-pregnant (N = 447)
Age (years)
Mean age (6SD) 26.3 (8.5) 31.5 (10.7)
Missing 1 (0.2%) 0
Dengue criteria
(WHO 1997)
Dengue fever 53 (53.5%) 364 (77.4%)
DHF 45 (45.5%) 78 (17.5%)
DSS 1 (1.0%) 5 (5.0%)
Hospitalization
Yes 61 (61.6%) 118 (26.4%)
No 3 (3.0%) 4 (0.9%)
Missing response 35 (35.4%) 325 (72.7%)
Death
Yes 3 (3.0%) 5 (1.1%)
No 78 (78.8%) 309 (69.1%)
Missing response 18 (18.2%) 133 (29.8%)
doi:10.1371/journal.pntd.0002217.t001
Table 2. Distribution according to the trimester of pregnant
women.
Dengue criteria (WHO 1997)
Dengue fever DHF/DSS
n(%) n(%)
Pregnant 53 (53.5) 46 (46.5)
First trimester 17 (32,0) 7 (15.2)
Second trimester 11 (20,8) 14 (30,4)
Third trimester 14 (26.4) 23 (50.0)
Trimester unknown 11 (20.8) 2 (4.4)
doi:10.1371/journal.pntd.0002217.t002
Table 3. Univariate and multivariate analyses.
DHF/DSS
OR (CI)
p-value
Univariate analysis
Pregnancy 3.80 (2.40–6.04) ,0.001
Age (15–49 years) 0.97 (0.95–0.98) ,0.001
Trimester
First trimester 1
Second trimester 3.10 (0.97–10.6) 0.06
Third trimester 3.98 (1.36–12.65) 0.01
Multivariate analysis
Pregnancy 3.38 (2.1–5.42) ,0.001
Age (15–49 years) 0.97 (0.95–0.99) 0.03
Trimester
First trimester 1
Second trimester 3.02 (0.94–10.37) 0.06
Third trimester 3.94 (1.33–12.69) 0.01
doi:10.1371/journal.pntd.0002217.t003
Dengue Infection Severity among Pregnant Women
PLOS Neglected Tropical Diseases | www.plosntds.org 3 May 2013 | Volume 7 | Issue 5 | e2217
introduces some limitations such as bias resulted from incomplete
data and possible misclassification. Although pregnant women
were more likely to be hospitalized for fever and illness in general
compared to their non-pregnant counterparts, it would be
expected a lower frequency of severity among this group as
pregnant women had a preventive hospitalization.
As all the uncompleted data about death were attributed to non-
pregnant women, the mortality rate among pregnant women
might still be underestimated.
SINAN has also been used in Brazil to conduct studies on
dengue [15]. Although citywide surveillance system of information
has no specific clinical plasma leakage signs data and may be
incomplete, it is a population-base registry from which maternal
dengue severity could be inferred by the access to dengue
classification. Further longitudinal studies are needed to confirm
these findings and to determine on how these two subgroups
presents clinically and how their presentations differ.
Supporting Information
Checklist S1 STROBE Checklist.
(DOC)
Author Contributions
Conceived and designed the experiments: PB . Performed the experiments:
CRM ESM PB. Analyzed the data: CRM ESM RBdO PB RDR.
Contributed reagents/materials/analysis tools: RBdO DPC MA. Wrote
the paper: CRM ESM PB RDR.
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