Symptomatic dengue infection during pregnancy and livebirth outcomes in Brazil, 2007–13: a retrospective observational cohort study

doi:10.1016/S1473-3099(17)30169-X

The Lancet Infectious Diseases

Volume 17, Issue 9, September 2017, Pages 949-956

https://doi.org/10.1016/S1473-3099(17)30169-X Get rights and content

Summary

Background

Dengue is a major public health challenge in Brazil. We assessed the relationship between symptomatic dengue infection during pregnancy and adverse birth outcomes in the country between 2007 and 2013.

Methods

We did a retrospective observational cohort study using information reported in the Brazilian national reportable disease information system (SINAN) and the livebirth information system (SINASC) databases. We probabilistically linked confirmed dengue-positive and dengue-negative pregnancies with live childbirths using Fine-Grained Record Integration and Linkage (FRIL) software. We also included an external reference population of randomly selected newborn babies. Pregnancy was adopted as the unit of analysis. We assessed the relationship between symptomatic dengue infection during pregnancy and adverse birth outcomes, using multivariable logistic regression adjusted for relevant covariates.

Findings

3898 dengue-positive pregnant women, 3165 dengue-negative women, and 3898 newborn babies from the reference population were included in the analysis. Preterm birth occurred in 322 (8·4%) of 3821 cases in the dengue-positive group versus 324 (10·4%) of 3101 in the dengue-negative group (unadjusted analysis: relative risk [RR] 0·81, 95% CI 0·70–0·93; adjusted analysis: odds ratio [OR] 1·26, 95% CI 1·06–1·49, p=0·006) and 349 (9·1%) of 3818 in the reference population (RR 0·92, 0·80–1·07; OR 0·98, 0·83–1·16, p=0·84). The prevalence of low birthweight (<2500 g) was similar for dengue-positive women and dengue-negative women (8·3% [322 of 3897] vs 9·8% [310 of 3163]; OR 1·17, 95% CI 0·99–1·39, p=0·07), and in the reference population (8·3% vs 9·0% [350 of 3895]; OR 1·00, 0·85–1·17, p=0·97). The prevalence of malformations did not differ significantly for the dengue-positive group (27 [0·7%] of 3789) versus the dengue-negative group (27 [0·9%] of 3059, p=0·51) or versus the reference population (32 [0·9%] of 3738, p=0·56).

Interpretation

In the adjusted analysis, the risk of preterm birth seems to be increased in women with symptomatic dengue infection during pregnancy. However, symptomatic dengue infection during pregnancy does not appear to be associated with congenital malformations or low birthweight.

Funding

Sanofi Pasteur.

Introduction

Dengue is the most important arboviral disease in the world because of its morbidity, mortality, and economic burden.1, 2 The virus is transmitted by Aedes spp mosquitoes and all four serotypes of the virus can cause symptomatic infections ranging from dengue fever to severe dengue, which can lead to death.³

In Brazil, the disease has become a major public health challenge, with 9 million probable cases, over 5200 deaths from 2002 to 2015, and an increase in the number of cases in children younger than 2 years, people older than 60 years, and pregnant women.4, 5, 6 Thus, it is important to monitor outbreaks of dengue to understand any new or unexpected outcomes associated with the disease. However, despite the hyperendemic transmission of dengue, only a few studies have investigated the association of symptomatic dengue infection during pregnancy with adverse fetal outcomes. They have shown no association with fetal outcomes or with premature birth and low birthweight. However, these studies had small sample sizes (n=202 for all studies combined).7, 8, 9 To our knowledge, no national or large investigations have been done to date.

The use of infectious disease surveillance data allows for a quick and comprehensive investigation of some uncertainties regarding this disease.¹⁰ Dengue fever has been a mandatorily notifiable disease in Brazil since 1986.¹¹ The dengue surveillance system relies on passive reporting of outpatients and those admitted to or treated in hospital with the use of standardised forms. Livebirths are also systematically registered in Brazil, including data on birth outcomes.¹² In this study, we used the well established national information systems in Brazil to assess the effect of symptomatic dengue infection during pregnancy on these birth outcomes, before the introduction of chikungunya and Zika viruses to this country.

Section snippets

Study design

We did a retrospective observational cohort study that was based on probabilistic record linkage between the national reportable disease information system (SINAN) and the livebirth information system (SINASC) databases in Brazil. SINAN collects information on a comprehensive set of communicable diseases, including dengue, whereas SINASC collects information on livebirth characteristics, including prenatal care and neonatal health. We restricted our study to data from 2007 to 2013, when a

Results

Among the 56 817 reported cases of dengue in pregnant women during the study period, 11 382 had laboratory-confirmed dengue (11 190 confirmed by IgM ELISA test, 133 by virus isolation, and 59 by RT-PCR) and 9351 had a negative serological test. The rest of the reported cases were excluded owing to the absence of a laboratory test. 885 records from SINAN and 1559 from SINASC were excluded because of duplication or inconsistencies. 4025 dengue-positive women were linked to livebirths, and 127

Discussion

We did a retrospective cohort study to investigate the association between reported symptomatic dengue infections during pregnancy and subsequent birth outcomes in women in Brazil. The unadjusted risk of premature birth in the dengue-positive group during the second trimester and across all trimesters aggregated was lower than that in the dengue-negative group. However, after adjustment for confounders, the risk of premature birth was higher in the dengue-positive group than in the

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Cited by (27)

Climate change and preterm birth: A narrative review
2022, Environmental Advances
The sizable and multifactorial risks to human health posed by climate change are both increasingly well understood and broadly accepted. One critical aspect of human health that has received comparatively scant attention in this area is the increased risk of preterm birth, deriving from the direct and indirect effects climate change. Preterm birth, delivery prior to 37 weeks’ completed gestation, impacts more than 15 million pregnancies every year. The healthcare costs of caring for preterm infants and their families exceed tens of billions of dollars annually. As such, prematurity conveys significant costs to preterm birth survivors, their families, and society.
Climate change is predicted to exert a host of direct and indirect impacts on pregnancy health that translate to an increased risk of preterm delivery, perinatal death, and long-term morbidity. We identified seven impacts of climate change, namely, temperature, precipitation, air quality, food insecurity, displacement, range of vector-borne diseases, and socio-economic inequality, that jointly and individually have the potential to convey an elevated risk of adverse pregnancy outcomes and preterm birth. We performed a literature review using these terms. We present data in a narrative review to highlight the material risk of shortened pregnancy duration posed by climate change. In particular, although targeted interventions may offset some impacts of climate change, it is increasingly apparent that the meta-system impacts exerted by climate change mean that effective and long-term actions by which a significant reduction in pregnancy health risks may be achieved require: (i) tackling the root cause of climate change itself; and (ii) considering vulnerable populations, such as pregnant women, in multisectorial climate adaptation plans. Given the potential risk posed to pregnancy health by preterm birth, we advocate for prematurity/pregnancy health to be considered as a critical factor in the assessment of climate change interventions.
Ebola, Dengue, Chikungunya, and Zika Infections in Neonates and Infants
2021, Clinics in Perinatology
Viral Hemorrhagic Fevers Other than Ebola and Lassa
2019, Infectious Disease Clinics of North America
Dengue vaccination during pregnancy – An overview of clinical trials data
2018, Vaccine
Citation Excerpt :
The largest study included in the analysis was a retrospective cohort study showing increased risk of preterm birth and low birth weight in infants born to women with symptomatic dengue infection during pregnancy in French Guiana [35]. A more recent retrospective cohort study based on two Brazilian national information system databases (2007–2013) found the risk of preterm birth to be higher in women with symptomatic dengue during pregnancy, with no association observed for low birth weight or congenital malformation [36]; while a smaller study based on 2008 data from Rio de Janeiro again supported a potential association between maternal disease specifically in the final period of gestation and adverse pregnancy outcomes (prematurity and low birth weight) [37]. Among the pregnancies (exposed or non-exposed) reported in the current analysis, there were no reported cases of concurrent dengue infection leading to hospitalisation or severe disease, probably due to the generally infrequent occurrence of severe dengue or dengue-related hospitalisation and the limited number of pregnancies reported.
The live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in several endemic countries and contraindicated during pregnancy. Inadvertent vaccination during pregnancy may occur during clinical trials that include women of childbearing age. The potential risk associated with dengue vaccination in pregnancy remains unknown. We describe pregnancy outcomes following inadvertent dengue vaccination in pregnancy from CYD-TDV trial data.
Data were collected from trials conducted as part of the CYD-TDV clinical development. Women who received CYD-TDV or placebo during the pre-specified pregnancy risk window (from 30 days before the date of their last menstrual period to end of pregnancy) were considered as exposed; pregnancies occurring in non-risk periods during the trials were considered to be non-exposed. Pregnancy losses were defined as abortion (spontaneous or unspecified), death in utero, and stillbirth.
615 pregnancies were reported from 19 CYD-TDV trials: 404 in the CYD-TDV arm, and 211 in the placebo arm. Exposure could not be determined for 7 pregnancies (5, CYD-TDV; 2, placebo). In the CYD-TDV arm, 58 pregnancies were considered as exposed. Most of these (n = 47, 81%) had healthy live births; 6 (10.3%) had pregnancy losses; 3 underwent elective termination and 2 had unknown outcome. In the placebo group, 30 pregnancies were considered exposed. Most of these (n = 25, 83%) had healthy births; 4 (13.3%) had pregnancy losses; and 1 had elective termination. Among non-exposed pregnancies, most resulted in healthy live births; 23/341 (6.7%) in the CYD-TDV group and 17/179 (9.5%) in the placebo group had pregnancy losses. Most reported pregnancy losses were in women considered high-risk for adverse pregnancy outcome, primarily due to young age.
In the small dataset assessed, no evidence of increased adverse pregnancy outcomes has been identified from inadvertent immunization of women in early pregnancy with CYD-TDV compared with the control group.
Symptomatic dengue infection during pregnancy and the risk of stillbirth in Brazil, 2006–12: a matched case-control study
2017, The Lancet Infectious Diseases
Citation Excerpt :
These studies could be done with a much smaller number of patients than was used here. According to a systematic review11 of studies of small sample size,11 a comment by Carles,30 and a study of similar Brazilian data,31 dengue infection during pregnancy is associated with adverse fetal outcomes, and severe forms of the disease carry a higher risk than less severe forms. This finding was supported by our study, in which the risk of stillbirth among women who had severe forms of dengue was almost three times that of those with mild disease.
Maternal infections during pregnancy can increase the risk of fetal death. Dengue infection is common, but little is known about its role in fetal mortality. We aimed to investigate the association between symptomatic dengue infection during pregnancy and fetal death.
We did a nested case-control study using obstetrician-collected data from the Brazilian livebirth information system (SINASC), the mortality information system (SIM), and the national reportable disease information system (SINAN). We identified all pregnancies ending in stillbirth and a random sample of livebirths between Jan 1, 2006, and Dec 31, 2012. We did linkage to determine which mothers were diagnosed with dengue infection during pregnancy. By use of stillbirths as cases and a sample of matched livebirths as a control, we calculated matched odds ratios (mORs) using conditional logistic regression adjusted for maternal age and education.
275 (0·2%) of 162 188 women who had stillbirths and 1507 (0·1%) of 1 586 105 women who had livebirths were diagnosed with dengue infection during pregnancy. Symptomatic dengue infection during pregnancy almost doubled the odds of fetal death (mOR 1·9, 95% CI 1·6–2·2). The increase in risk was similar when analyses were restricted to laboratory-confirmed cases of dengue infection (1·8, 1·4–2·4). Severe dengue infection increased the risk of fetal death by about five times (4·9, 2·3–10·2).
Symptomatic dengue infection during pregnancy is associated with an increased risk of fetal death. We recommend further epidemiological and biological studies of the association between dengue and poor birth outcomes to measure the burden of subclinical infections and elucidate pathological mechanisms.
Brazilian National Council for Scientific and Technological Development, Horizon 2020.
Dengue virus infection during pregnancy increased the risk of adverse fetal outcomes? An updated meta-analysis
2017, Journal of Clinical Virology
Citation Excerpt :
Table 2). Ten studies [17,23,25–30,33,34], including three prospective cohort 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).
To evaluate the effect of maternal dengue virus (DENV) infection during pregnancy in premature birth, low birth weight, miscarriage and stillbirth.
Systematic electronic literature searches were conducted including PubMed, Medline, Embase, Web of science, Scopus and the Cochrane Library database, up until July 5, 2017. Effect sizes were estimated by using the relative risk (RR) or odds ratio (OR) with theirs corresponding 95% confidence interval (CI). Subgroup analyses were conducted for study design (prospective or retrospective) and clinical symptom of participants (symptomatic or asymptomatic). Statistical analysis was conducted by STATA 12.0.
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 participants 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.
Current evidence did not suggest that maternal DENV infection during pregnancy might increase the risk of premature birth, low birth weight, miscarriage and stillbirth.

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ArticlesSymptomatic dengue infection during pregnancy and livebirth outcomes in Brazil, 2007–13: a retrospective observational cohort study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design

Results

Discussion

Int J Infect Dis

Eur J Obstet Gynecol Reprod Biol

J Hosp Infect

Lancet Infect Dis

J Pediatr

J Clin Virol

The global distribution and burden of dengue

Nature

Dengue: a continuing global threat

Nat Rev Microbiol

Dengue: guidelines for diagnosis, treatment, prevention, and control

Description of the current epidemiological trends of dengue in the Americas