This study identified evidence of elevated arboviral infection in a cohort of parturition mothers at a national referent hospital in western El Salvador. Approximately 24.2% were DENV and/or ZIKV IgM + at the time of childbirth, suggesting arboviral infection during their pregnancy. The majority of seropositive flavivirus cases came from Sonsonate department, where spatially significant clusters were identified in Sonsonate and Cuisnahuat municipalities, Fig. 2C. This result is consistent with 2022 MOH reports of elevated risk for infection in Sonsonate municipality [26]. We also identified a spatial outlier, a municipality with a significantly higher proportion of cases than neighboring municipalities, in Salcoatítan.
Results of this study further revealed that those participants who had MOH fumigation within the home in the last year had approximately 5 times the risk of seropositivity, compared to those who did not report MOH fumigation. MOH fumigation services are targeted neighborhood-level efforts to eliminate Aedes spp. mosquitoes along with other infectious disease vectors, following suspected or confirmed human vector-borne infection. In contrast, participants who were visited by the MOH for mosquito abatement assistance were 70% less likely to be flavivirus IgM seropositive. As hypothesized, spatial proximity to known cases of vector-borne infection in areas already vulnerable to these diseases was a risk factor for IgM + in this study. Mosquito abatement methods typically include insecticide spraying, larvicide donations for commonly used water storage containers, and environmental control (e.g. removal of mosquito breeding habitats). These results indicate favorable reach of the MOH mosquito abatement campaigns, and that enhanced abatement and fumigation efforts should be targeted in neighborhoods with historically high arboviral case burdens.
Pregnancy complications and adverse neonatal birth outcomes including premature birth, low birthweight, and NICU admission, occurred frequently among flavivirus seropositive mothers. However, no statistically significant relationships were found among IgM positivity and adverse health outcomes. Adverse neonatal outcomes were also frequent among seronegative mothers in this study, making clarification of flavivirus IgM + cases and health outcomes challenging.
No statistically significant associations were found between assessed poverty indicators: water source in the home, housing materials, ITN use, or substandard housing. However, this particular region is highly economically vulnerable with homogenous substandard living conditions, and a high multidimensional poverty index above national averages [27]. Ahuachapan and Sonsonate rank among the highest in country for inadequate housing materials, food insecurity, and crowding [27]. Over 25% of houses in this region lack access to potable water and more than 50% lack access to sanitation services [27]. Therefore, precise socioeconomic and standard of living comparisons were difficult to compare between groups due to the highly underserved nature of the entire study population. Given the overall high rate of multidimensional poverty in this region and the substandard living conditions that yield supportive mosquito breeding habitats, the risk of arboviral infection exists in this particularly vulnerable national region.
Despite ZIKV case reports significantly lower in national surveillance reporting compared to DENV nationally, our study found a high rate of ZIKV IgM + in perinatal women [23]. A 2019 study modelling ZIKV transmission risk in Latin America using a maximum entropy approach identified El Salvador to be among a few countries in the region at particularly high risk for transmission [21]. In the same year of our study, 2022, the Ministry of Health reported 172 ZIKV cases with 6 cases reported among pregnant women in the country: one of these six cases occurred in Sonsonate. As nearly 80% of ZIKV infections present asymptomatically, it is likely the incidence of infection is higher than MOH reports based on clinical syndrome. Further, 62 cases of ZIKV were identified among infants < 1 year of age [24, 26], shown in Additional File 2. This highlights the potential that a proportion of these cases may have resulted from congenital transmission.
The challenges with serologic cross-reactivity between these two infections is also well known [28]. Therefore, it is possible that some ZIKV or DENV cases in this study resulted from this cross-reactivity when the other flavivirus was, in fact, the causal agent. Despite this possibility, we found a much higher flavivirus IgM seroprevalence among this perinatal group than previously expected based on identified cases in recent years by the MOH. Dengvaxia DENV vaccine was not previously nor currently available in El Salvador at the time of participant sample collection, thus excluding the possibility of detecting vaccine derived antibodies vs. natural infection. Therefore, this study warrants future investigations of flavivirus in pregnancy, particularly in vulnerable regions of this highly endemic country.
In addition, ZIKV and DENV surveillance within the human population is not routinely conducted in El Salvador, therefore symptomatic cases presenting to health clinics are typically syndromically identified without laboratory confirmation. Likely due to overextension of the public health sector during the COVID-19 pandemic, surveillance and testing resources have been particularly strained in recent years. In 2021, only 2.7% of suspected DENV cases received confirmatory testing [24, 29]. Only 13.5% of 16,542 suspected cases of DENV received PCR or IgM testing in 2022 [26]. The number of suspected ZIKV infections that received clinical laboratory testing nationally is not published. Suspected and confirmed national cases of DENV and ZIKV can be found in Additional File 3. Due to the challenges in feasibility for sustained human surveillance along with the high rate of asymptomatic presentation of these flaviviruses, it is difficult to assess the true incidence of ZIKV and DENV in El Salvador. This study provides evidence that infections may be occurring more frequently than previously described and could present a continued threat to maternal-neonatal health in this country.
Our data warrants the need for education and laboratory screening for arboviral infections in the perinatal period, as infectious diseases and congenital malformations are the two leading causes of neonatal death in El Salvador, making this a major issue of public health importance [30]. Identification of pregnancies with high-risk of congenital transmission (early term ZIKV infection or late term DENV infection) may aid in early case detection of vertically infected neonates, to plan for proper continuum of neonatal care. Maternal screening could also benefit clinical management of maternal cases, particularly with DENV where maternal mortality risk is increased three-fold.
Almost all perinatal women in this study received at least one prenatal care visit in all three trimesters of pregnancy (96%), despite many women living in rural areas. This finding is in part, likely due to the recently enacted maternal-infant health care laws El Salvador. The 2022 “Ley Nacer con Cariño” (translated as Born with Care) has created novel infrastructure for perinatal health promotion and enhanced care for mothers and infants [25]. The government provides continuing education for OBGYN’s and healthcare professionals and quality inspections of labor and delivery units. The law also refocuses efforts towards enhanced prenatal care, promoting healthy fetal development, and comprehensive education for mothers and partners surrounding lactation and infant care.
As rural women often receive care by a health officer home visit, this health campaign presents a unique opportunity to incorporate further perinatal screenings for vertically transmissible infectious pathogens. Currently, HIV and syphilis are the only infectious pathogens mandatorily screened for in prenatal care [25], and screening for flaviviral infections may also be warranted in certain high-risk regions of the country. This point of intervention could also be utilized for expanded mosquito abatement and promotion of ITN-use adherence to aid in prevention among high-risk vulnerable women. Neighborhoods necessitating fumigation following a case of vector-borne disease could be prioritized for maternal flavivirus screening so that positive pregnancies can be monitored to aid in assuring positive outcomes for mother and baby. Spatially significant clustering of flaviviral IgM positivity occurred in Sonsonate and Cuisnahuat municipalities in Sonsonate department. These high-risk regions could be targeted for future arboviral infection studies and enhanced prenatal screening and education campaigns.
Though significant statistical associations were not found between seropositivity and adverse neonatal health outcomes, neonatal health status was assessed only at the time of birth. The authors hypothesize that due to a lack of hospital protocol to test for ZIKV infection combined with a limited neonatal assessment at birth, subclinical pathology cannot be excluded among these infants. APGAR and a basic physical check are the only two neonatal indicators assessed at this large referent hospital: neurologic function or head pathology beyond head circumference measurement are non-standard. Due to the high rate of ZIKV maternal positivity identified in this study during a MOH reported non-ZIKV outbreak year, further studies are warranted regarding arboviral infection in pregnancy in this region of El Salvador. Collectively this evidence suggests a possibility that congenital infections are ongoing, and maternal-fetal cases may be going undetected due to a lack of surveillance and the high rate of asymptomatic or non-specific hallmark symptomology.
Results of this study identified nearly one-quarter of women with evidence of a recent flavivirus infection at parturition, as evidenced by IgM + screening tests. As DENV and ZIKV IgM antibodies generally persist for only a few months following acute infection, results of this study suggest IgM + women in this study were potentially infected during their pregnancy. However, ZIKV and DENV IgM antibody decline and duration post-infection is not well characterized, particularly among adults, and few studies have attempted to quantify antibody kinetics for these infections [28, 31]. However, IgM following primary infection has been described more than one year following infection making temporality difficult to assess. In El Salvador, DENV is highly endemic with routine ZIKV outbreaks, thus this adult population is likely to have had prior arboviral infections. Therefore, a presumed shorter IgM duration (one representing infection within the third trimester of infection) is biologically possible in this population.
Future studies to clarify IgM antibody decline are critical in world regions where flavivirus is highly endemic, particularly in those countries where resource constraints limit confirmatory testing to primarily serologic methods. Further human surveillance studies are warranted among asymptomatic populations to clarify the true burden of these commonly asymptomatic arboviral infections, and to understand risk for vulnerable populations such as pregnant women.
This study screened banked maternal serum samples for flavivirus infection at parturition and analyzed health surveys to determine risk factors and health outcomes associated with infection. As 75–80% of ZIKV and DENV cases present asymptomatically, the true incidence of these infections is difficult to conclude. Further, there is a limited understanding of the clinical implications of asymptomatic flavivirus infection among pregnant women. This study provides a unique approach to better understanding both the incidence of asymptomatic infections and maternal-fetal outcomes among women with recent subclinical flavivirus infection during pregnancy.
This study has a few limitations worth noting. Specific pathogen serological results were not confirmed with plaque-reduction neutralization test nor by polymerase chain reaction, prompting statistical analysis to be performed among the collective flavivirus group due to inability to rule out potential antibody cross-reaction. Therefore unintended misclassification of DENV infections as ZIKV, based on IgM results alone, could dilute the ability to detect a significant relationship between congenital anomalies and maternal ZIKV infection. Secondly, due to the overall low number of municipalities and distribution of cases within our departments, the spatial statistic run to address case clustering should be taken as exploratory only. Future studies with higher recruitment across this region should be conducted to provide more rigorous autocorrelation and hotspot analyses. Additionally, incident infection timing cannot not be confirmed by DENV and ZIKV IgM antibody status; however, as these pathogens’ antibodies generally persist for a few weeks to months following acute infection [34, 35], it is possible that perinatal women in this study were infected during their pregnancy. Future investigations of antibody kinetics among susceptible adult populations are needed to assess infection temporality. Improved serologic assays that can be reliably employed in low-and-middle income countries, where these infections endemically circulate, are also critical to alleviate negative outcomes that stem from missed diagnoses of these infections.
Add Comment