Abstract
The purpose of this study was to determine if there is an association between maternal herpes simplex virus (HSV) infection and pre-eclampsia/eclampsia or gestational hypertension. The US Nationwide Inpatient Sample database was searched for women aged 15–44 years who delivered in a hospital between 2005 and 2014. The patients were categorized into those with and without HSV and pre-eclampsia/eclampsia and gestational hypertension were compared between the groups. The analytic sample size (n=8 264 076) was equivalent to a population-based sample size of 40 653 030 patients. After adjusting for significant variables including age, race, income, insurance status, diabetes mellitus (DM), gestational DM, obesity, and multiple gestations, multivariate regression analysis indicated that HSV was associated with a higher OR for gestational hypertension (adjusted OR 1.038; 95% CI 1.004 to 1.072). However, HSV was not associated with pre-eclampsia/eclampsia (OR 1.001; 95% CI 0.968 to 1.035) in univariate regression analysis. The results of the current study suggest that HSV infection is associated with gestational hypertension but not pre-eclampsia. Given the prevalence of HSV infection and its potential association with hypertensive disorders of pregnancy, further study of HSV and hypertension in pregnancy is warranted.
Significance of this study
What is already known about this subject?
Gestational hypertension occurred after 20 weeks’ gestation in a previously normotensive woman.
Aberrant activation of inflammatory cascades was associated with pregnancy complications.
Maternal infections were associated with hypertensive disorders of pregnancy.
What are the new findings?
The percentage of women who gave birth with HSV increased from 0.8% in 2005 to 2.4% in 2014.
Maternal herpes simplex virus (HSV) infection was associated with gestational hypertension.
But, HSV infection was not associated with pre-eclampsia/eclampsia.
How might these results change the focus of research or clinical practice?
The risk of gestational hypertension in women with HSV should be examined in clinical practice.
Introduction
Pre-eclampsia is characterized by new onset hypertension (blood pressure >140/90 mm Hg) and proteinuria after 20 weeks’ gestation in pregnant women who were previously normotensive.1 Pre-eclampsia occurs in 2%–8% of all pregnancies and is a leading cause of maternal and neonatal morbidity and mortality worldwide.2 3 Gestational hypertension, or pregnancy-induced hypertension (PIH), is also characterized by the development of new hypertension after 20 weeks’ gestation in a previously normotensive woman without the presence of proteinuria or other signs of pre-eclampsia.1
Despite decades of research, the pathophysiology and causative factors of pre-eclampsia and PIH have remained elusive.4–7 A number of mechanisms have been postulated, and it is now generally accepted that the etiology of pre-eclampsia and PIH is multifactorial and involves both maternal and placental contributions.4–7
An inflammatory response is required for proper embryo implantation and placentation.7. However, aberrant activation of inflammatory cascades has been shown to be associated with pregnancy complications.4 5 Over the past 1–2 decades, a growing body of literature has suggested that maternal infections by bacteria, viruses, and parasites and the subsequent maternal inflammatory response play an important role in the development of pre-eclampsia.8–10
Herpes simplex virus (HSV) is a member of the herpes virus family that affects humans. HSV-1 primarily affects the orofacial region producing cold sores, while HSV-2 is a sexually transmitted disease that produces genital lesions.11 Both are highly contagious and infections are lifelong. Although the exact prevalence of HSV infection is extremely difficult to estimate because a large number of cases go unreported, the WHO has estimated that 3.7 billion people under the age of 50 (67%) have HSV-1 infection, and 417 million people globally 15–49 years of age (11%) have HSV-2 infection.11 A study has suggested an association between HSV infection and essential hypertension.12 However, studies regarding HSV and hypertensive disorders of pregnancy are few.
Thus, the purpose of this study was to determine if there is an association between maternal HSV infection and pre-eclampsia and/or PIH using a nationwide, population-based US database, the Nationwide Inpatient Sample (NIS).
Methods
Data source
The NIS is the largest all-payer US inpatient care database, and it contains over a hundred clinical and non-clinical data elements from approximately 8 million hospital stays each year. Included in these data elements are primary and secondary diagnoses, primary and secondary procedures, admission and discharge status, patient demographic data, expected payment source, length of stay, and hospital characteristics. All patients are considered for inclusion. The most recent NIS database contains data from about 1050 hospitals from 44 states in the US sampled to approximate a 20% stratified sample of US community hospitals as defined by the American Hospital Association. The NIS was developed as part of the Healthcare Cost and Utilization Project (HCUP), which is sponsored by the Agency for Healthcare Research and Quality.
This study obtained the certificate number, HCUP-74GZR8817, and conforms to the data-use agreement for the NIS from the HCUP Project.
Study population and definitions
The first step of this study was to identify patients who delivered an infant in a hospital between 2005 and 2014 in HCUP-NIS database. This was done by identifying records of women aged 15–44 years with a delivery hospitalization (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code V27, 65X.X, 66X.X). These codes are exclusive to births occurring during a hospital admission.
We then excluded women with chronic hypertension (women who had hypertension before pregnancy or before 20 weeks’ gestation) by using ICD-9 code 401–405 to focus only on those who developed hypertension after 20 weeks’ gestation. Finally, we identified women with a HSV infection who delivered an infant by identifying admissions containing the ICD-9 diagnostic code 054.XX. Patients without these codes were categorized as without HSV infection.
Variable definitions
The dependent variables were gestational hypertension, which was defined using ICD-9-CM codes 642.0, 642.2, 642.3, and pre-eclampsia/eclampsia, which was defined using ICD-9-CM codes 642.4, 642.5, and 642.6. The independent variables (covariates) were age, race, income status, insurance status, and hospital location. The following potential confounding variables were also examined: pre-gestational diabetes, gestational diabetes, obesity, alcohol abuse, history of smoking, and multiple gestations.
Statistical analysis
Differences in categorical variables between NIS discharges with and without HSV were examined using the Rao-Scott Χ2 test, and data were expressed as unweighted counts (weighted %). Univariate and multivariate logistic regression models were used to determine whether HSV was associated with gestational hypertension or pre-eclampsia/eclampsia. Variables having a p value <0.05 in the univariate analysis were selected and evaluated by the multivariate logistic regression model. Since the NIS database is a 20% sample of the US yearly inpatient admissions, weighted samples (DISCWT), stratum (NIS_STRATUM), and cluster (HOSPID) were used to produce national estimates for all analyses. All statistical assessments were two-sided and evaluated at the 0.05 level of significance. Statistical analyses were performed using the statistical software package SPSS complex sample module V.22.0.
Results
A total of 8 436 558 females aged between 15 and 44 years with a delivery hospitalization were identified in the NIS during the period 2005–2014. A total of 172 482 women with the history of hypertension were excluded. Using discharge weights, the analytic sample size (n=8 264 076) was equivalent to a population-based sample size of 40 653 030 patients in the USA.
The percentage of women who gave birth with HSV increased from 0.8% in 2005 to 2.4% in 2014 (p<0.001; figure 1). The characteristics of patients with and without HSV are shown in table 1. There were significant differences in age, race, insurance status, living location, and the comorbidities of DM, gestational DM, obesity, alcohol abuse, smoking, and multiple gestations between patients with and without HSV (all, p<0.001).
The ORs for the probability of gestational hypertension with point estimates and 95% CI are shown in table 2. Age, race, income, insurance status, DM, gestational DM, obesity, smoking, multiple gestation, and HSV were significantly associated with gestational hypertension according to univariate logistic regression. After adjusting for significant variables including age, race, income, insurance status, DM, gestational DM, obesity, and multiple gestation, multivariate regression analysis indicated that HSV was still associated with a higher OR of gestational hypertension (adjusted OR 1.038; 95% CI 1.004 to 1.072).
Univariate logistic regression showed that age, race, income, living location, DM, gestational DM, obesity, smoking, and multiple gestations were significantly associated with pre-eclampsia/eclampsia (table 3). However, HSV was not associated with pre-eclampsia/eclampsia (OR 1.001; 95% CI 0.968 to 1.035) in univariate logistic regression analysis (table 3).
Discussion
The main finding of this population-wide database study was that maternal HSV infection was associated with the development of gestational hypertension, but not with pre-eclampsia/eclampsia.
Decades of research have led to the identification of some risk factors for gestational hypertension and pre-eclampsia/eclampsia, and many causal models have been proposed, but the pathophysiological mechanism(s) have yet to be determined.1 13 Studies in the past decade have suggested that the immune system and the inflammatory response play a leading role in the development of hypertension in pregnancy.4 5 7 Some studies have suggested that the underlying cause of hypertension in pregnancy is an imbalance of angiogenic factors, and inflammation enhances this underlying pathology.6 In any event, the possibility that inflammation involved in the development of gestational hypertension and pre-eclampsia/eclampsia has resulted in examining if infectious causes of inflammation are associated with hypertension in pregnancy.
Few studies have explored the relationship between HSV infection and hypertension. An early study by Sun et al 12 investigated patients (male and female) with essential hypertension and normotensive controls and found that HSV-2 infection was an independent risk factor for essential hypertension after adjusting for covariates including age, male sex, smoking, body mass index, dyslipidemia, diabetes, and coronary heart disease. A recent case-controlled study reported that HSV-2 as well as rubella seropositivity was associated with pre-eclampsia.14 Another population-based study reported that fetal exposure to herpes virus infection was associated with pregnancy-induced hypertensive disorders and preterm birth.15 However, lack of association between HSV infection and pre-eclampsia has also been reported.9 16 Furthermore, no significant differences in maternal plasma seropositivity for HSV-2 immunoglobulin (Ig)M and IgG between the pre-eclampsia and control groups were observed.17 In agreement with the above studies,9 15–17 the current NIS study found significant association between HSV with gestational hypertension, but not with pre-eclampsia/eclampsia.
Although the association between HSV and hypertensive disorders of pregnancy has not been extensively studied, studies have reported bacterial, viral, and parasitic infections are associated with increased risk of developing pre-eclampsia.8–10 Some specific infections found to be associated with the development of pre-eclampsia include Chlamydia trachomatis,16 Helicobacter pylori,18 Chlamydia pneumoniae,17 19 urinary tract infections,20 21 infection associated with periodontal disease,9 cytomegalovirus,10 and parasitic infections including Plasmodium spp and Toxoplasma gondii.10
The current study has certain inherent strengths and limitations. The primary strength of this study is that it includes a large number of patients from all geographical regions in the USA. The NIS encompasses 20% of all discharges in the USA and is thus a respectable representative sample of the US population. With respect to limitations, the diagnoses were identified based on ICD codes only, and coding errors and misclassifications might exist.
The severity of comorbidities was unknown based on the ICD-coded system and might confound the results. The cross-sectional design of this study can only demonstrate associations; therefore, causation cannot be determined.
In conclusion, the results of the current study suggest that HSV infection is associated with gestational hypertension but not pre-eclampsia. Given the prevalence of HSV infection and its potential association with hypertensive disorders of pregnancy, further study of HSV and hypertension in pregnancy is warranted.
Footnotes
LS and YW contributed equally.
Contributors LS supervised the study, contributed to the critical revision of the manuscript and is the guarantor of integrity of the entire study. YW drafted the manuscript and did the statistical analysis. Both authors contributed to the conception and design; acquisition of data and analysis and interpretation of data. Both authors have read and approved the final version to be submitted.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.