Among those patients with severe sepsis, organ dysfunction included respiratory dysfunction (34.2%), coagulation abnormalities (19.2%), renal dysfunction (16.4%), cardiovascular dysfunction (11.6%), hepatic dysfunction (10.3%), and central nervous system dysfunction (8.2%).
In this study, we used a large, representative sample of hospitalizations in the United States to estimate the frequency, independent associations, and temporal trends for severe sepsis during hospitalization for delivery. Even with adjustment for risk factors, the frequency of severe sepsis increased from 1:15,385 (95% CI, 1:12,987–1:18,519) to 1:7246 (95% CI, 6329–8333) during our 11-year study period. Thus, pregnancy-related severe sepsis is a growing source of severe maternal morbidity and mortality in the United States.
The increases in severe sepsis and sepsis-related mortality are consistent with the published UK experience.1 The increase in the United Kingdom was attributed to increased Group A β-hemolytic streptococcus and Escherichia coli infections, microbial resistance, and population factors of increasing maternal age, obesity, cardiovascular disease, migrant population, smoking, and poor overall health.1 Our U.S. data demonstrate that the increase in severe sepsis persisted despite adjusting for maternal age, presence of comorbidities, CD, multiple gestation, reliance on Medicaid, and other factors. This increase may have been due to similar factors as those identified in the United Kingdom, but not measured with administrative data such as increasing microbial resistance, obesity, smoking, substance abuse, and poor general health.
Chronic comorbid conditions such as congestive heart failure, chronic liver disease, chronic renal disease are well-established risk factors for sepsis in the general population and demonstrated associations with severe sepsis.14,15 SLE may increase the risk secondary to the use of steroids and immunosuppressive medications and immunologic abnormalities of the disease process itself.16–18 While women with these conditions are a relatively small proportion of the delivering population, the magnitude of risk associated with these conditions suggests prompt consideration of the diagnosis and treatment of sepsis in patients with these conditions.
Population-attributable fractions for all factors that had a significant association with severe sepsis were calculated to identify the most important sources of the population burden of severe sepsis in pregnancy. Importantly, none of the population-attributable fractions exceeded 5.9%, suggesting that sepsis often occurs in the absence of a recognized risk factor. This underscores the need for developing systems of care that increase sensitivity for disease detection across the entire population.
Common organisms implicated in severe sepsis in the current analysis were E coli, staphylococcus, streptococcus, and Gram-negative organisms. The underlying organism and information about antimicrobial resistance was missing from a large proportion of cases. More research on the causative organisms for maternal sepsis in the United States is warranted.
Consistent with the pattern observed for adverse maternal outcomes, advanced maternal age, African American race, and Medicaid insurance, all demonstrate independent associations with severe sepsis in multivariable analysis.19,20 Women from vulnerable socioeconomic backgrounds may have an increased risk for a range of adverse outcomes, including severe sepsis.21 Small volume hospitals demonstrated decreased risk of severe sepsis compared with larger centers; this may reflect small hospitals transferring women developing critical illness to larger centers for delivery.
Severe sepsis obstetric associations include rescue cerclage, prophylactic cerclage, retained products of conception, PPROM, and multiple gestation. Rescue cerclage conferred a greater risk than prophylactic cerclage. Information regarding whether providers evaluated for the presence of intrauterine infection, used ultrasonography before rescue cerclage placement, or a specific PPROM management strategy is not available from the NIS data. Therefore, the likelihood by which rescue cerclage and PPROM lead to maternal sepsis and the modifying effect of specific management strategies cannot be determined from this study. Finally, the higher risk of severe sepsis among women with multiple gestation may result from complications more commonly seen in this population such as PPROM, preterm labor, endometritis, postpartum hemorrhage, or gestational diabetes.22–25
The secondary multivariable analysis found preterm delivery, postpartum hemorrhage, stillbirth, and CD during labor to be associated with severe sepsis. In contrast, elective CD was found to be protective. Within the database, no temporal relation to diagnosis codes are provided; thus, we were unable to determine which diagnosis occurred first. Preterm delivery, postpartum hemorrhage, stillbirth, and CD could be associated with severe sepsis by reverse causality. For example, a patient who develops severe sepsis is more likely to have a CD. That said, CD is the most important risk factor associated with postpartum endometritis; endometritis is the etiology for 8.6% of severe sepsis cases in our dataset.26,27 Future prospective studies to define the role of intrapartum CD as a risk factor for severe sepsis are needed.
Our study findings should be interpreted in light of its design. The NIS does not capture many clinical details, such as Acute Physiology and Chronic Health Evaluation (APACHE II) scores or Sequential Organ Failure Assessment (SOFA) scores, measures of severity of critical illness. Certain conditions such as obesity are undercoded. In addition, while sepsis can occur during the antepartum or postpartum period, we focused our analysis on patients admitted to the hospital for delivery. To analyze associations, we sought a sample of otherwise healthy controls. Because the NIS only captures hospitalizations, this analysis is only possible during the delivery hospitalization. Administrative data cannot be verified and may result in underestimation or overestimation of severe sepsis cases. It is also possible that a patient could have suffered acute end-organ injury first, and subsequently developed sepsis; this patient would be categorized as having severe sepsis in our study. Nevertheless, independent of whether the end-organ injury was causally related to sepsis or the sepsis was superimposed on preexisting organ dysfunction, clinical experience suggests that these patients are a particularly high-risk group whose prognosis is worse than those who have sepsis in the absence of end-organ injury. Furthermore, our operational definition of severe sepsis as diagnostic codes indicating sepsis along with codes indicating end-organ injury is a standard approach in the intensive care unit epidemiology literature.7–9,15
It is possible that changes in coding practice increased documentation of severe sepsis without an actual increase in clinical acuity. The study period coincided with the initiation of the Surviving Sepsis Campaign (2004)28 and a landmark paper by Rivers et al. (2001)29 highlighting the importance of early goal-directed therapy. Increased intensity in sepsis coding has demonstrated a shift in the primary diagnostic code from the underlying etiology (e.g., pneumonia with sepsis listed as a secondary diagnosis) to sepsis as the primary diagnosis.30 To attenuate this error, a sepsis composite was considered which documented across any of the diagnostic positions rather than strictly the primary position.
In conclusion, maternal severe sepsis and sepsis-related deaths are increasing in the United States. Severe sepsis often occurs in the absence of a recognized risk factor and underscores the need for developing systems of care that increase sensitivity for disease detection across the entire population. Patients with conditions of congestive heart failure, chronic liver disease, chronic renal disease, and SLE have an increased risk of severe sepsis. Physicians should enhance surveillance in patients with risk factors for developing infection and institute early treatment when signs of sepsis are emerging.
Name: Melissa E. Bauer, DO.
Contribution: Melissa Bauer contributed to the study design and prepared the manuscript.
Attestation: Melissa Bauer approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.
Name: Brian T. Bateman, MD, MSc.
Contribution: Brian Bateman contributed to the study design and critically edited the manuscript.
Attestation: Brian Bateman approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Samuel T. Bauer, MD.
Contribution: Samuel Bauer was the obstetrical consultant and critically edited the manuscript.
Attestation: Samuel Bauer approved the final manuscript.
Name: Amy M. Shanks, MS.
Contribution: Amy Shanks contributed to study design, performed statistical analyses, and edited the manuscript.
Attestation: Amy Shanks approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Jill M. Mhyre, MD.
Contribution: Jill Mhyre contributed to the study design and critically edited the manuscript.
Attestation: Jill Mhyre approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
The authors thank Mary Lou V. H. Greenfield, MPH, MS, RN (Senior Research Associate, Department of Anesthesiology, University of Michigan Health System, Ann Arbor, MI), Tiara Forsyth, BS (Research Assistant, Department of Anesthesiology, University of Michigan Health System), and Chloe Powell, BSE (Research Assistant, Department of Anesthesiology, University of Michigan Health System) for their support in the preparation of this manuscript.
a Overview of the Nationwide Inpatient Sample (NIS). Available at: http://www.hcup-us.ahrq.gov/reports/methods/2003_2.jsp. Accessed February 5, 2013.
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