Journal of Clinical Virology 94 (2017) 42–49

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Journal of Clinical Virology

journal homepage: www.elsevier.com/locate/jcv

Review

Dengue virus infection during pregnancy increased the risk of adverse fetal MARK
outcomes? An updated meta-analysis
⁎
Yi-Quan Xionga, Yun Moa, Ting-Li Shib, Lin Zhuc, Qing Chena,
a
Department of Epidemiology, School of Public Health, Southern Medical University, Guangdong Provincial Key Laboratory of Tropical Disease Research, Guangzhou,
China
b
The Third People's Hospital of Hainan Province, Hainan, China
c
Preventive Medicine (Innovation Excellence Class), School of Public Health, Southern Medical University, Guangzhou, China

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: To evaluate the effect of maternal dengue virus (DENV) infection during pregnancy in premature
Dengue birth, low birth weight, miscarriage and stillbirth.
Pregnancy outcome Methods: Systematic electronic literature searches were conducted including PubMed, Medline, Embase, Web of
Preterm birth science, Scopus and the Cochrane Library database, up until July 5, 2017. Effect sizes were estimated by using
Low birth weight
the relative risk (RR) or odds ratio (OR) with theirs corresponding 95% confidence interval (CI). Subgroup
Miscarriage
analyses were conducted for study design (prospective or retrospective) and clinical symptom of participants
Meta-analysis
(symptomatic or asymptomatic). Statistical analysis was conducted by STATA 12.0.
Results: The initial systematic literature searches identified 1048 studies. After screening, fourteen studies were
included. The pooled results did not suggest maternal DENV infection might increase the risk of adverse fetal
outcomes with a pooled RR of 0.96 (95% CI: 0.85–1.09, I2 = 49.6%) for premature birth, RR of 0.99 (95%CI:
0.87–1.12, I2 = 35.1%) for low birth weight, OR of 1.77 (95% CI: 0.99–3.15, I2 = 17.5%) for miscarriage and
RR of 3.42 (95% CI: 0.76–15.49, I2 = 54.8%) for stillbirth. Subgroup analysis of studies in symptomatic par-
ticipants still did not indicate DENV infection appeared to be a risk factor for premature birth, low birth weight
and miscarriage with pooled effect size of 0.99 (95% CI: 0.87–1.13, I2 = 49.3%), 1.22 (95% CI: 0.827–1.80,
I2 = 55.1%) and 1.19 (95% CI: 0.56–2.55, I2 = 4.7%), respectively.
Conclusions: Current evidence did not suggest that maternal DENV infection during pregnancy might increase
the risk of premature birth, low birth weight, miscarriage and stillbirth.

1. Introduction
Dengue is one of the most important mosquito-borne viral diseases
and the incidence of dengue has risen in these decades worldwide [1].
Dengue is a threat to health and a burden on health services and
economies in most tropical and subtropics countries in the world [2].
The World Health Organization (WHO) estimates that 50–100 million
dengue infections occur each year [3]. Dengue infection was caused by
4 serotypes of dengue virus (DENV) and primarily transmitted by Aedes
aegypti or Aedes Albopictus [4]. Infected by DENV, the individuals may
appear fever, body aches, leukopenia, and other symptoms of acute
viral infection. However, the outcomes of DENV infection are various
and range from asymptomatic, to mild and hospitalization. Most par-
ticipants who became infected by DENV were either asymptomatic or
minimally symptomatic [5].
DENV infection is generally encountered in children and
adolescents [6], but adults can also be infected [7–9]. Although a small
proportion of dengue infections will present complications, pregnant
women seem to be more likely to present more severe forms of dengue
infection than general population [10]. Recent evidence suggests that
maternal DENV infection during pregnancy may affect the fetal out-
comes, such as premature birth, low birth weight and miscarriage
[11–14]. For example, Adam and colleagues [14] reported the preterm
birth rate of 78 laboratory confirmed dengue cases in Sudan was 18%
and the rate of low birth weight was 24%. Since most of related studies
were case reports and case series and because of the lack of comparative
studies, it is still controversial whether maternal DENV infection is a
risk factor for adverse pregnancy outcomes [15]. A meta-analysis con-
ducted by Paixão and colleagues [16] indicated that symptomatic
dengue during pregnancy might be a risk factor for fetal adverse out-
comes with a pooled OR of 2.50 (95% CI: 1.44–4.34) and 1.84 (95% CI:
1.04–3.25) for premature birth and low birth weight, respectively.

⁎
Corresponding author at: Department of Epidemiology, School of Public Health, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, China.
E-mail address: qch.2009@163.com (Q. Chen).

http://dx.doi.org/10.1016/j.jcv.2017.07.008
Received 20 April 2017; Received in revised form 10 July 2017; Accepted 12 July 2017
1386-6532/ © 2017 Elsevier B.V. All rights reserved.
Y.-Q. Xiong et al.
However, there were two limits in this study. This study failed to in-
clude two comparative articles [17,18] in the meta-analysis. Further-
more, the authors used Mantel and Haenszel method to calculate the
pooled effect size when the heterogeneity between studies was statis-
tically significant. The two limits may confuse the association between
maternal DENV infection during pregnancy and fetal outcomes. Hence,
we conducted an updated meta-analysis, with a summary of all pub-
lished studies, to evaluate the effect of maternal DENV infection during
pregnancy in premature birth, low birth weight, miscarriage and still-
birth.
2. Methods
This meta-analysis is conducted in accordance with the Preferred
Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)
guidelines [19].
2.1. Literature search
Systematic electronic literature searches were conducted including
PubMed, Medline, Embase, Web of science, Scopus and the Cochrane
Library database, up to July 5, 2017. The searches were limited to
human studies without language restriction. We used the following
keywords separately and in combinations: “dengue,” “dengue hemor-
rhagic fever,” “pregnancy,” “preterm birth,” “abortion,” “low birth
weight,” and “miscarriage.” Additional references were identified by
manual searching of the reference lists of review articles and selected
articles.
2.2. Inclusion and exclusion criteria
Studies were screened for eligibility if they met the following cri-
teria: (1) reported the adverse fetal outcomes (premature birth, or low
birth weight, or miscarriage, or stillbirth) of DENV pregnancy infection;
(2) reported corresponding effect estimates or sufficient data for their
calculation; (3) cohort study, case-control study, or cross-sectional
study design which provide effective control group; and (4) DENV in-
fection was detected during pregnancy. Studies were excluded if they
were: (1) review articles, case reports, case series, editorials, opinions;
and (2) without effective control groups to calculate effect estimates.
2.3. Data selection and extraction
Citations were merged in Endnote (version X7) to facilitate man-
agement and data extraction. Two authors independently evaluated all
retrieved articles by title, abstract, and full text according to the above
inclusion and exclusion criteria. Any disagreement was resolved by
consensus. We used a uniform questionnaire, which was developed
before searching the literature, to extract information from each eli-
gible study. Extracted information included: first author, publication
year, country of origin, study design, dengue detection method,
symptomatic or asymptomatic, number of dengue infected participants
with or without adverse fetal outcomes (premature birth, or low birth
weight, or miscarriage, or stillbirth), corresponding RRs or ORs, and
95% CI values, and statistical adjustments for confounding factors.
When data were reported from overlapping study samples (e.g., mul-
tiple publications from the same study), the most recent and compre-
hensive report was considered.
2.4. Quality assessment
The quality of case control and cohort studies was assessed by the
Newcastle–Ottawa Scale (NOS) [20,21]. In this scale, studies are scored
across three categories: selection of subjects, comparability of study
groups, and assessment of outcome/exposure. The rating system was
used to indicate the quality of a study, with a maximum score of nine.
43
Journal of Clinical Virology 94 (2017) 42–49
Studies were graded on an ordinal scoring scale, where higher scores
representing studies of higher quality. We defined a study as high
quality when the NOS score was not less than six.
2.5. Statistical analysis
Relative risk (RR) was selected as the effect size when only cohort
study was included in pooled analysis. When pooled analysis included
cohort study, case-control study and cross-sectional study, a pooled
odds ratio (OR) was calculated. Inter-study heterogeneity was esti-
mated by the I2 statistic, and significant heterogeneity was defined as
I2 ≥ 50%. Pooled results and corresponding 95% CIs were calculated
with a fixed effects model (Mantel and Haenszel method) when het-
erogeneity was not significant (I2 < 50%); otherwise, a random-effects
model (DerSimonian and Laird method) was applied. Subgroup ana-
lyses were conducted for study design (prospective or retrospective)
and clinical symptom of participants (symptomatic or asymptomatic).
Sensitivity analyses by sequentially removing individual eligible studies
were used to evaluate whether any single study dominated the results of
the meta-analyses. Sensitivity analyses were also conducted by re-
moving the low quality studies (NOS score less than six) from the
analysis. A meta-regression analysis was performed to explore potential
inter-study heterogeneity. Finally, publication bias was assessed by
visual inspection of funnel plots and Egger’s linear regression [22].
Statistical analyses were conducted using STATA 12.0 (Stata Corp LP,
College Station, TX).
3. Results
Description of included studies
The initial systematic literature searches identified 1048 studies.
Most ineligible studies were excluded based on the information in the
title or abstract. After screening, fourteen studies [17,18,23–34] were
assessed for eligibility and were included in this meta-analysis. The
selection process was shown in Fig. 1. The main characteristics of in-
cluded studies were described in Table 1. Eleven studies reported
[17,23,25–29,31–34] the impact of DENV infection on the risk of pre-
mature birth and ten studies reported [17,23,25–30,33,34] the impact
of DENV infection on the risk of low birth weight. Five studies
[18,24,26,29,32] and two studies [28,29] reported the association be-
tween maternal DENV infection during pregnancy and miscarriage and
stillbirth, respectively. Eight studies [17,18,23,26,27,30,33,34] were
conducted in Latin America and three studies [24,25,29] were con-
ducted in Asia. Data of the study conducted by Baudin and colleagues
[32] was obtained from the authors by e-mail. At the same time, we
treated this study [32] as a retrospective comparative study, since the
authors retrospectively analyzed the association between DENV infec-
tion in blood samples of pregnant women and the following fetal out-
comes. The quality of most included studies was high, but NOS score of
two cohort studies [26,27] and one case-control study [18] were less
than six (Table 1).
3.1. Association between maternal DENV infection and premature birth
Eleven studies [17,23,25–29,31–34], including two prospective
cohort studies, eight retrospective cohort studies, and one cross-sec-
tional study, with a total of 357983 participants, reported the impact of
DENV infection on risk of premature birth. The pooled results indicated
that there was no significant association between DENV infection and
premature birth with RR of 0.96 (95% CI: 0.85–1.09, I2 = 49.6%)
(Fig. 2). In addition, subgroup analyses showed that when only nine
symptomatic studies [17,23,26–29,31,32,34] were included, the DENV
infection still did not appear to be a risk factor for premature birth with
RR of 0.99 (95% CI: 0.87–1.13, I2 = 49.3%). The pooled RRs of two
prospective studies [25,29] and nine retrospective studies
[17,23,26–28,31–34] were 0.64 (95% CI: 0.34–1.21, I2 = 0.0%) and
Y.-Q. Xiong et al.
1.267 (95% CI: 0.83–1.94, I2 = 55.5%), respectively. (Table 2).
3.2. Association between maternal DENV infection and low birth weight
Ten studies [17,23,25–30,33,34], including three prospective co-
hort studies and seven retrospective cohort studies, with a total of
358443 participants, reported the impact of DENV infection on risk of
low birth weight. The pooled result suggested that there was no positive
association between DENV infection and low birth weight (RR = 0.99,
95% CI: 0.87–1.12, I2 = 35.1%) (Fig. 3). Similarly, When only seven
symptomatic studies [17,23,26–29,34] were included, the accordingly
pooled RR was 1.22 (95% CI: 0.83–1.80, I2 = 55.1%) (Table 2). Sub-
group analyses showed that the pooled RRs of prospective cohort stu-
dies and retrospective cohort studies were 0.61 (95% CI: 0.31–1.22,
I2 = 31.6%) and 1.01 (95% CI: 0.89–1.14, I2 = 44.4%), respectively.
(Table 2).
3.3. Association between maternal DENV infection and miscarriage
Five studies [18,24,26,29,32] including 960 participants reported
the impact of DENV infection on risk of miscarriage. The pooled OR was
1.77 (95% CI: 0.99–3.15, I2 = 17.5%) (Fig. 4), which suggested there
was no significantly association between maternal DENV infection and
miscarriage. The results of three symptomatic studies [26,29,32], and
two cohort studies [26,29],were consistent with the overall effect with
pooled results of 1.19 (95% CI: 0.56–2.55, I2 = 4.7%) and 1.00 (95%
CI: 0.43–2.31, I2 = 25.1%). However, the result of two case-control
studies and a cross-sectional study [18,24,32], indicated a significantly
positive association between DENV infection and miscarriage weight
(OR = 2.89, 95% CI: 1.32–6.30, I2 = 0.0%) (Table 2).
3.4. Association between maternal DENV infection and stillbirth
The association between maternal DENV infection and stillbirth was
relatively unexplored. Two cohort studies [28,29] with a total of 572
participants, indicated that there was no significantly association be-
tween maternal DENV infection and stillbirth with pooled RR of 3.42
(95% CI: 0.76–15.49, I2 = 54.8%).
44
Journal of Clinical Virology 94 (2017) 42–49
Fig. 1. Flow diagram of the studies identified in the meta-
analysis.
3.5. Heterogeneity analysis
Meta-regression analysis was conducted to explore the inter-study
heterogeneity in the analysis of impact of DENV infection on premature
birth. Four variables were included in the meta-regression analysis: (1)
study design (prospective cohort study vs. retrospective cohort study);
(2) clinical symptom of participants (symptomatic vs. asymptomatic);
(3) number of participants (≥100 vs. < 100), and (4) country of origin
(Latin America vs. other regions). The meta-regression analysis failed to
reveal any factor that contributed to the heterogeneity.
3.6. Sensitivity analysis
Sensitivity analysis was performed by sequentially removing in-
dividual eligible studies. We observed that no individual study altered
the overall significance of the RRs in the analyses of the impact of DENV
infection on premature birth and low birth weight. However, the result
indicated when removed the study conducted by Chansamouth and
colleagues [29], the association between DENV infection and mis-
carriage became significantly with pooled OR of 3.04 (95% CI:
1.43–6.46, I2 = 0.0%). In addition, we removed the two low quality
studies [26,27] (NOS score less than six) from the analysis of associa-
tion between DENV infection and premature birth and low birth weight,
the pooled results of remaining studies were consistent with that of all
studies included, which did not suggest that the DENV infection was a
risk factor for premature birth and low birth weight.
3.7. Published bias
No significant asymmetry was found in funnel plots. Egger’s linear
regression test also showed there was no significant publication bias on
the association between maternal DENV infection and premature birth,
low birth weight and miscarriage with P value of 0.25, 0.27 and 0.23,
respectively.
4. Discussion
Previous studies reported that maternal DENV infection might
 Y.-Q. Xiong et al.
Table 1
Basic characteristic of the eligible studies.

Author (Year) Country Study design Dengue detection method Clinical symptom of Adverse fetal outcomes Confounding NOS
participants score

Ribeiro (2016) [23] Brazil retrospective cohort IgM/PCR/viral isolation symptomatic premature birth, low birth weight NA 7
study
Tan (2008) [25] Malaysia prospective cohort IgM asymptomatic premature birth,low birth weight NA 8
study
Restrepo (2004) [26] Colombia retrospective cohort IgM/PCR/viral isolation symptomatic premature birth,low birth NA 5
study weight,miscarriage,
Restrepo (2003) [17] Colombia retrospective cohort IgM symptomatic premature birth, low birth weight NA 6
study
Barroso (2010) [27] Cuba retrospective cohort IgM/IgG symptomatic premature birth, low birth weight NA 5
study
Friedman (2014)a French Guiana retrospective cohort IgM/PCR/viral isolation/ symptomatic premature birth, low birth weight, premature birth: aOR = 3.34 (1.13, 9.89),low birth weight: 9
[28] study NS1 antigen stillbirth aOR = 2.23 (1.01, 4.90);adjusted factor: anemia, maternal ethnicity,
gravid, interpregnancy interval, mothers age
Chansamouth (2016) Laos prospective cohort IgM/PCR/NS1 antigen symptomatic premature birth, low birth weight, all participants with fever and without septicemia, pyelonephritis, 7
45

[29] study miscarriage, stillbirth rickettsioses, leptospirosis, malaria, dengue fever, japanese
encephalitis virus infection and hepatitis E Virus infection
Leite (2014) [30] Brazil prospective cohort IgM/PCR asymptomatic low birth weight NA 6
study
Angarita (2013) [31] Venezuela retrospective cohort IgM symptomatic premature birth NA 6
study
Baudin (2016) [32] Sudan cross-section study IgM symptomatic premature birth, miscarriage NA 6
Tan (2012) [24] Malaysia prospective case- IgM and/or NS1 antigen asymptomatic miscarriage miscarriages: aOR = 4.2 (1.2–14); adjusted factor: maternal age, 6
control study gestational age, parity and ethnicity
Nishioka (1998) [18] Brazil case-control study NA asymptomatic miscarriage miscarriages: aOR = 2.46(0.88-6.83), adjusted factor: smoking, 4
schooling, exanthema, fogging, hypertension, age, gestational age,
oral contraceptive
Feitoza (2017) [33] Brazil retrospective cohort IgM or clinical/ NA premature birth, low birth weight NA 8
study epidemiological criterion
Nascimento (2017) Brazil retrospective cohort IgM/PCR/viral isolation symptomatic premature birth, low birth weight premature birth: aOR = 0.98 (0.83-1.16),low birth weight: 8
[34] study aOR = 1.00 (0.85-1.17);adjusted factor: antenatal care visits, age of

Journal of Clinical Virology 94 (2017) 42–49

the mother, marital status, and mode of delivery

NOS, Newcastle-Ottawa Scale; aOR, adjusted OR; NA, not available.

a
preterm birth in this study was defined as < 37 weeks of gestational age, including miscarriages.
Y.-Q. Xiong et al. Journal of Clinical Virology 94 (2017) 42–49

Fig. 2. Forest plot of the impact of maternal DENV

infection on risk of premature birth. (A)
Symptomatic studies; (B) No symptomatic or unclear
studies.

Table 2
Subgroup analysis of association between maternal DENV infection and adverse fetal outcomes.

Study included Number of participants OR/RR 95% CI Heterogeneity (I2) (%)

Premature birth
Clinical symptom
Symptomatic and asymptomatic 11 357983 0.96 0.85−1.09 49.6
Only symptomatic 9 354474 0.99 0.87−1.13 49.3
Study design
Prospective study 2 2695 0.64 0.34−1.21 0.0
Retrospective study 9 355288 1.27 0.83−1.94 55.5

Low birth weight

Clinical symptom
Symptomatic and asymptomatic 10 358443 0.99 0.87−1.12 35.1
Only symptomatic 7 354467 1.22 0.83−1.80 55.1
Study design
Prospective study 3 3164 0.61 0.31−1.22 31.6
Retrospective study 7 355279 1.01 0.89−1.14 44.4

Miscarriage
Clinical symptom
Symptomatic and asymptomatic 5 960 1.77 0.99−3.15 17.5
Only symptomatic 3 436 1.19 0.56−2.55 4.7
Study design
Cohort study 2 306 1.00 0.43−2.31 25.1
Non-cohort study 3 654 2.89 1.32−6.30 0.0

RR, relative risk; OR, odds ratio; 95% CI: 95% confidence interval

increase the risk of adverse pregnancy outcomes such as premature
birth, low birth weight and miscarriage [15,16,26,28]. However, the
results in this meta-analysis did not suggest that maternal DENV in-
fection could increase the risk of adverse pregnancy outcomes with a
pooled RR of 0.96 (95 % CI: 0.85–1.09) for premature birth, RR of 0.99
(95% CI: 0.87–1.12) for low birth weight, OR of 1.77 (95% CI:
0.99–3.15) for miscarriage and RR of 3.42 (95% CI: 0.76–15.49) for
stillbirth. In addition, subgroup analysis in studies with symptomatic
participants still did not indicate that DENV infection appeared to be a
risk factor for premature birth, low birth weight and miscarriage with
pooled effect size of 0.99 (95% CI: 0.87–1.13), 1.22 (95% CI:
0.827–1.80), and 1.19 (95% CI: 0.56–2.55), respectively (Table 2).
Two systematic reviews have been published in 2010 and 2016 to
assess the association between maternal DENV infection during preg-
nancy and adverse fetal outcomes [15,16]. Sawyer and colleagues [15]
summarized the available evidence and concluded that there is a risk of
vertical transmission of DENV infection, but whether maternal infection
is a significant risk factor for adverse pregnancy outcomes remains
unclear. Paixao and colleagues [16] conducted a meta-analysis of eight
comparative studies and concluded that symptomatic dengue fever
during pregnancy might be a risk factor for preterm birth and low birth
weight with pooled OR of 2.50 (95% CI 1.44–4.34) and 1.84 (95% CI
1.04–3.25), respectively. However, the conclusion that symptomatic
dengue fever might be a risk factor for preterm birth and low birth
weight did not reappear in our results. Considering the more compre-
hensive studies included in our study, we did not suggest that symp-
tomatic dengue fever during pregnancy might be associated with pre-
term birth, low birth weight, miscarriage and stillbirth.
In the sensitivity analysis section, we observed when the study
conducted by Chansamouth and colleagues [29] was removed, the as-
sociation between DENV infection and miscarriage became significantly
with pooled OR of 3.04 (95% CI: 1.43–6.46). Chansamouth and

46
Y.-Q. Xiong et al.
colleagues [29], conducted a hospital-based prospective study in two
central hospitals in Vientiane City (Laos), between 2006 and 2010.
They analyzed the effect of single dengue fever on 250 pregnancy
outcomes by eliminated other infection diseases, for instance, malaria,
leptospirosis, scrub typhus, murine typhus and typhoid. The risk of
dengue fever during pregnancy on premature birth, low birth weight
and miscarriage in the study were lower than 1, with RRs of 0.76 (95%
CI: 0.38–1.52), 0.01 (95% CI: 0.005–1.43) and 0.80 (95% CI:
0.32–1.98), respectively. Considering that the quality of this study was
not low (NOS score = 7) and when this study was included, the inter-
study heterogeneity was not significant in the miscarriage (I2 = 17.5%)
analysis, so we did not exclude this study in the analyses.
As is known, many factors could influence the pregnancy outcomes,
such as age of mother, ethnic origin, psychological state of the mother,
smoking, alcohol consumption and a number of infections (malaria,
brucellosis, human immunodeficiency virus, influenza virus, human
papillomavirus and so on) [35–39]. Tan and colleagues [24] conducted
a prospective case-control study involving 116 miscarriage cases and
47
Journal of Clinical Virology 94 (2017) 42–49
Fig. 3. Forest plot of the impact of maternal DENV
infection on risk of low birth weight. (A)
Symptomatic studies; (B) No symptomatic or unclear
studies.
341 controls to establish the relationship of recent dengue infection and
miscarriage. The authors indicated that recent dengue infections were
more frequently detected in women presenting with miscarriage than in
controls whose pregnancies were viable with a RR of 3.1 (95% CI:
1.0–10). Meanwhile, the authors conducted an adjusted analysis by
controlled maternal age, gestational age, parity and ethnicity and the
result still indicated recent dengue infection was a risk factor for mis-
carriage with a more moderate RR of 4.2 (95% CI: 1.2–14). Similarly, in
a retrospective cohort study [28], the investigators adjusted anemia,
maternal ethnicity, gravid, interpregnancy interval and mothers’ age in
their adjusted model and indicated that symptomatic dengue infection
significantly increased the rate of preterm birth and low birth weight in
pregnancy women with adjusted ORs of 3.34 (95% CI: 1.13, 9.89) and
2.23 (95% CI: 1.01, 4.90), respectively. However, the unadjusted ORs
of preterm birth and low birth weight were 1.92 (95% CI: 0.88, 4.39)
and 2.06 (95% CI: 1.03, 4.10), which were inconsistent with the ad-
justed results. Since most of studies included in our analysis did not
report the associated risk factors except for DENV infection, we could
Fig. 4. Forest plot of the impact of maternal DENV
infection on risk of miscarriage. (A) Symptomatic
studies; (B) No symptomatic studies.
Y.-Q. Xiong et al.
only calculate unadjusted pooled RRs/ORs. The unadjusted pooled re-
sults in our study should be interpreted with caution. Some known and
unknown confounding factors in studies may reduce the risk of dengue
infection during pregnancy for adverse pregnancy outcomes. Further
large epidemiologic research with controlled confounding is required to
clarify whether dengue infection during pregnancy indeed increase
adverse pregnancy outcomes.
Besides DENV, some other arbovirus infection may also affect fetal
outcomes, for instance, Zika, chikungunya and yellow fever viruses.
Recent evidence suggested that ZIKV can replicate in pluripotent (am-
niotic stem) cells involved in early-stage embryo development and
might be associated with miscarriage in addition to microcephaly
[40–42]. For chikungunya virus, previous studies reported this virus
can cross the placenta in the first and second trimester leading to fetal
infection and miscarriage [43]. However, a large prospective study
conducted by Fritel and colleagues [44] indicated no differences in
congenital anomalies, antepartum vaginal bleeding, fetal growth re-
striction, intrauterine fetal demise, or preterm delivery in women with
and without chikungunya fever. Since the cross-reaction was found
between DENV and Zika and other flavivirus, and dengue, Zika and
other arbovirus could exist at the same time in some tropical and
subtropical region, more specific detection method should be used to
define case in the future studies.
Some limitations of this meta-analysis should be addressed. First,
moderate inter-study heterogeneity was found in the meta-analysis.
Although, we performed subgroup analysis and meta-regression, the
results did not identify all source of heterogeneity among studies.
Second, DENV infection may cause varying degrees of effect in different
stages of pregnancy. We did not distinguish the risk of DENV infection
for adverse pregnancy outcomes in first, second or third trimesters,
since the time of adverse pregnancy outcomes were reported in-
sufficiently in original studies. Third, since the cross-reaction was found
between DENV and other flavivirus, most of included original studies
which used ELISA (IgM) to diagnose DENV infection might introduce
some false positives.
5. Conclusions
Current evidence did not suggest that maternal DENV infection
during pregnancy might increase the risk of premature birth, low birth
weight, miscarriage and stillbirth.
Competing interests
None declared.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Ethical approval
Not required.
References
[1] WHO. Global strategy for dengue prevention andcontrol 2012–2020. http://
appswhoint/iris/bitstream/10665/75303/1/9789241504034_engpdf?ua=1.
[2] S. Bhatt, P.W. Gething, O.J. Brady, J.P. Messina, A.W. Farlow, et al., The global
distribution and burden of dengue, Nature 496 (2013) 504–507.
[3] WHO, Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control, World
Health Organization and the Special Programme for Research and Training in
Tropical Diseases, Geneva, 2009.
[4] J.V. Murray, C.C. Jansen, P. De Barro, Risk associated with the release of
Wolbachia-infected Aedes aegypti mosquitoes into the environment in an effort to
control dengue, Front. Public Health 4 (2016) 43.
[5] D.S. Burke, A. Nisalak, D.E. Johnson, R.M. Scott, A prospective study of dengue
48
Journal of Clinical Virology 94 (2017) 42–49
infections in Bangkok, Am. J. Trop. Med. Hyg. 38 (1988) 172–180.
[6] S.B. Halstead, Dengue in the Americas and Southeast Asia: do they differ? Rev.
Panam. Salud Publica 20 (2006) 407–415.
[7] C.C. Wang, I.K. Lee, M.C. Su, H.I. Lin, Y.C. Huang, et al., Differences in clinical and
laboratory characteristics and disease severity between children and adults with
dengue virus infection in Taiwan, 2002, Trans. R. Soc. Trop. Med. Hyg. 103 (2009)
871–877.
[8] T.M. Sharp, E. Hunsperger, G.A. Santiago, J.L. Munoz-Jordan, L.M. Santiago, et al.,
Virus-specific differences in rates of disease during the 2010 Dengue epidemic in
Puerto Rico, PLoS Negl. Trop. Dis. 7 (2013) e2159.
[9] S.S. Sam, S.F. Omar, B.T. Teoh, J. Abd-Jamil, S. AbuBakar, Review of Dengue he-
morrhagic fever fatal cases seen among adults: a retrospective study, PLoS Negl.
Trop. Dis. 7 (2013) e2194.
[10] A.F. Argolo, V.C. Feres, L.A. Silveira, A.C. Oliveira, L.A. Pereira, et al., Prevalence
and incidence of dengue virus and antibody placental transfer during late preg-
nancy in central Brazil, BMC Infect. Dis. 13 (2013) 254.
[11] C. Basurko, G. Carles, M. Youssef, W.E. Guindi, Maternal and fetal consequences of
dengue fever during pregnancy, Eur. J. Obstet. Gynecol. Reprod. Biol. 147 (2009)
29–32.
[12] N.A. Ismail, N. Kampan, Z.A. Mahdy, M.A. Jamil, Z.R. Razi, Dengue in pregnancy,
Southeast Asian J. Trop. Med. Public Health 37 (2006) 681–683.
[13] R. Waduge, G.N. Malavige, M. Pradeepan, C.N. Wijeyaratne, S. Fernando, et al.,
Dengue infections during pregnancy: a case series from Sri Lanka and review of the
literature, J. Clin. Virol. 37 (2006) 27–33.
[14] I. Adam, A.M. Jumaa, H.M. Elbashir, M.S. Karsany, Maternal and perinatal out-
comes of dengue in PortSudan, Eastern Sudan, Virol. J. 7 (2010) 153.
[15] S.H. Pouliot, X. Xiong, E. Harville, V. Paz-Soldan, K.M. Tomashek, et al., Maternal
dengue and pregnancy outcomes: a systematic review, Obstet. Gynecol. Surv. 65
(2010) 107–118.
[16] E.S. Paixao, M.G. Teixeira, C. Costa Mda, L.C. Rodrigues, Dengue during pregnancy
and adverse fetal outcomes: a systematic review and meta-analysis, Lancet Infect.
Dis. 16 (2016) 857–865.
[17] B.N. Restrepo, D.M. Isaza, C.L. Salazar, J.L. Ramirez, G.E. Upegui, et al., Prenatal
and postnatal effects of dengue infection during pregnancy, Biomedica 23 (2003)
416–423.
[18] A. Nishioka Sde, F.R. Nunes-Araujo, W.P. Pires, F.A. Silva, H.L. Costa, Yellow fever
vaccination during pregnancy and spontaneous abortion: a case-control study, Trop.
Med. Int. Health 3 (1998) 29–33.
[19] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, P. Group, Preferred reporting items
for systematic reviews and meta-analyses: the PRISMA statement, J. Clin.
Epidemiol. 62 (2009) 1006–1012.
[20] A. Stang, Critical evaluation of the Newcastle-Ottawa scale for the assessment of the
quality of nonrandomized studies in meta-analyses, Eur. J. Epidemiol. 25 (2010)
603–605.
[21] G.A. Wells, B. Shea, D. O'Connell, J. Peterson, V. Welch, et al., The Newcastle-
Ottawa Scale (NOS) for Assessing the Quality If Nonrandomized Studies in Meta-
analyses, (2009) http://wwwohrica/programs/clinical_epidemiology/.
[22] M. Egger, G. Davey Smith, M. Schneider, C. Minder, Bias in meta-analysis detected
by a simple, graphical test, BMJ 315 (1997) 629–634.
[23] C.F. Ribeiro, V.G. Lopes, P. Brasil, L.E. Silva, P.H. Ribeiro, et al., Dengue during
pregnancy: association with low birth weight and prematurity, Rev. Inst. Med. Trop.
Sao Paulo 58 (2016) 8.
[24] P.C. Tan, M.Z. Soe, K. Si Lay, S.M. Wang, S.D. Sekaran, et al., Dengue infection and
miscarriage: a prospective case control study, PLoS Negl. Trop. Dis. 6 (2012) e1637.
[25] P.C. Tan, G. Rajasingam, S. Devi, S.Z. Omar, Dengue infection in pregnancy: pre-
valence, vertical transmission, and pregnancy outcome, Obstet. Gynecol. 111
(2008) 1111–1117.
[26] B.N.I. Restrepo, Maria Diana, Clara Lina Salazar, José Luis Ramírez, Ruth
Emilia Ramírez, et al., Dengue y embarazo en Antioquia, Colombia, Rev. Fac. Nac.
22 (2004) 7–14.
[27] L.R. Barroso, I.D. Betancourt, Y.F. Saeta, M.M. Navarro, G.D. Guerra, Repercusión
del dengue serotipo 3 sobre el embarazo y producto de la concepción, Rev. Cuba
Obstet. Ginecol. 36 (2010) 42–50.
[28] E.E. Friedman, F. Dallah, E.W. Harville, L. Myers, P. Buekens, et al., Symptomatic
Dengue infection during pregnancy and infant outcomes: a retrospective cohort
study, PLoS Negl. Trop. Dis. 8 (2014) e3226.
[29] V. Chansamouth, S. Thammasack, R. Phetsouvanh, V. Keoluangkot, C.E. Moore,
et al., The aetiologies and impact of fever in pregnant inpatients in Vientiane, Laos,
PLoS Negl. Trop. Dis. 10 (2016) e0004577.
[30] R.C. Leite, A.I. Souza, P.M. Castanha, M.T. Cordeiro, C.T. Martelli, et al., Dengue
infection in pregnancy and transplacental transfer of anti-dengue antibodies in
Northeast, Brazil, J. Clin. Virol. 60 (2014) 16–21.
[31] L.C.A. Romero Angarita, Vielma Silvana, Magdalena Correa, María Inés Odreman,
Perinatal transmision of dengue virus from mother to infant during pregnancy,
Arch. Venez. Pueric. Pediatr. 76 (2013) 99–104.
[32] M. Baudin, A.M. Jumaa, H.J. Jomma, M.S. Karsany, G. Bucht, et al., Association of
Rift Valley fever virus infection with miscarriage in Sudanese women: a cross-sec-
tional study, Lancet Glob. Health 4 (2016) e864–e871.
[33] H.A.C. Feitoza, S. Koifman, R.J. Koifman, V. Saraceni, Dengue infection during
pregnancy and adverse maternal, fetal, and infant health outcomes in Rio Branco,
Acre State, Brazil, 2007–2012, Cad. Saude Publica 33 (2017) e00178915.
[34] L.B. Nascimento, C.M. Siqueira, G.E. Coelho, J.B. Siqueira Jr, Symptomatic dengue
infection during pregnancy and livebirth outcomes in Brazil, 2007-13: a retro-
spective observational cohort study, Lancet Infect. Dis. (2017), http://dx.doi.org/
10.1016/S1473-3099(17)30169-X.
[35] S. Giakoumelou, N. Wheelhouse, K. Cuschieri, G. Entrican, S.E. Howie, et al., The
Y.-Q. Xiong et al.
role of infection in miscarriage, Hum. Reprod. Update 22 (2016) 116–133.
[36] P.L. Xiao, Y.B. Zhou, Y. Chen, M.X. Yang, X.X. Song, et al., Association between
maternal HIV infection and low birth weight and prematurity: a meta-analysis of [41]
cohort studies, BMC Pregnancy Childbirth 15 (2015) 246.
[37] Q.T. Huang, S.S. Wei, M. Zhong, L.L. Hang, Y.Y. Xu, et al., Chronic hepatitis B
infection and risk of preterm labor: a meta-analysis of observational studies, J. Clin. [42]
Virol. 61 (2014) 3–8.
[38] Q.T. Huang, M. Zhong, Y.F. Gao, L.P. Huang, Q. Huang, et al., Can HPV vaccine
have other health benefits more than cancer prevention? A systematic review of [43]
association between cervical HPV infection and preterm birth, J. Clin. Virol. 61
(2014) 321–328.
[39] M.J. Silva, G.L. Florencio, J.R. Gabiatti, R.L. Amaral, J. Eleuterio Junior, et al., [44]
Perinatal morbidity and mortality associated with chlamydial infection: a meta-
analysis study, Braz. J. Infect. Dis. 15 (2011) 533–539.
[40] A.A. van der Eijk, P.J. van Genderen, R.M. Verdijk, C.B. Reusken, R. Mogling, et al.,
49
Journal of Clinical Virology 94 (2017) 42–49
Miscarriage associated with Zika virus infection, N. Engl. J. Med. 375 (2016)
1002–1004.
B. Schaub, A. Monthieux, F. Najihoullah, C. Harte, R. Cesaire, et al., Late mis-
carriage: another Zika concern? Eur. J. Obstet. Gynecol. Reprod. Biol. 207 (2016)
240–241.
M. Sarno, G.A. Sacramento, R. Khouri, M.S. do Rosario, F. Costa, et al., Zika virus
infection and stillbirths: a case of hydrops fetalis, hydranencephaly and fetal de-
mise, PLoS Negl. Trop. Dis. 10 (2016) e0004517.
S.K. Dotters-Katz, M.R. Grace, R.A. Strauss, N. Chescheir, J.A. Kuller, Chikungunya
fever: obstetric considerations on an emerging virus, Obstet. Gynecol. Surv. 70
(2015) 453–457.
X. Fritel, O. Rollot, P. Gerardin, B.A. Gauzere, J. Bideault, et al., Chikungunya virus
infection during pregnancy, Reunion, France, 2006, Emerg. Infect. Dis. 16 (2010)
418–425.