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Necrotizing Fasciitis: Association with Pregnancy-related Risk Factors Early in Life

Background: Pregnancy-related risk factors for necrotizing fasciitis are poorly understood. We investigated pregnancy-related characteristics associated with the long-term risk of developing necrotizing fasciitis, a rare life-threatening infectious disease. Methods: We analyzed a longitudinal cohort of 1,344,996 parous women in Quebec, Canada between 1989 and 2020. The main exposure measures included complications of pregnancy such as gestational diabetes, preterm delivery, metabolic disorder, and other maternal characteristics. We followed the women over time to identify future hospitalizations for necrotizing fasciitis up to three decades after delivery. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association of pregnancy characteristics with risk of necrotizing fasciitis in time-varying Cox proportional hazards regression models. Results: A total of 420 women were hospitalized for necrotizing fasciitis during follow-up, including 83 (19.8%) with diabetes-related necrotizing fasciitis. The incidence of necrotizing fasciitis was elevated for women with gestational diabetes (2.9 per 100,000 person-years), preterm delivery (3.2 per 100,000 person-years), and metabolic disorders (5.4 per 100,000 person-years), compared with no pregnancy complication (1.1 per 100,000 person-years). Compared with no pregnancy complication, gestational diabetes was associated with 1.87 times the risk (95% CI 1.38-2.53), preterm delivery with 2.10 times the risk (95% CI 1.65-2.66), and metabolic disorder with 3.72 times the risk (95% CI 2.92-4.74) of developing necrotizing fasciitis over time. Pregnancy complications were more strongly associated with the risk of necrotizing fasciitis 5 years or more after delivery. Conclusions: Complications of pregnancy may be associated with the long-term risk of necrotizing fasciitis in women.


INTRODUCTION
Necrotizing fasciitis is a rare but serious soft tissue infection with an incidence between 0.3 to 15 cases per 100,000 population [1]. Patients at greater risk of necrotizing fasciitis are not fully characterized, although known risk factors include trauma, recent surgery, immunosuppression, diabetes, obesity, and kidney disease [2][3][4]. Pregnant women are more likely to develop necrotizing fasciitis postpartum [5], with the risk appearing greater following cesarean section [6]. Some data suggest that postpartum hemorrhage, preterm birth, and cesarean section are associated with greater odds of sepsis up to 9 months after delivery [7,8]. While pregnancy appears to be an important contributor to severe infections, the possibility that adverse pregnancy outcomes are associated with the long-term risk of necrotizing fasciitis has not been studied.
Adverse pregnancy outcomes are risk factors for less severe postpartum infections [9][10][11]. Preeclampsia is associated with urinary tract infections the first month postpartum [9], and manual placenta removal and chorioamnionitis are associated with postpartum endometritis [10,11]. While the relationship with rare infectious diseases has not been studied, adverse pregnancy outcomes such as gestational diabetes and preeclampsia are associated with the development of type 2 diabetes, a known risk factor for necrotizing fasciitis [12,13]. The close relationship between pregnancy complications and metabolic disorders later in life suggests that pregnancy outcomes could predict the long-term risk of necrotizing fasciitis. We assessed whether complications such as preterm birth and gestational diabetes were associated with the future risk of necrotizing fasciitis in a population of parous women.

Study Design and Population
We carried out a longitudinal cohort study of 1,344,996 women who gave birth in Quebec, Canada between 1989 and 2019. We retrieved the cohort from the Maintenance and Use of Data for the Study of Hospital Clientele registry that contains discharge summaries for all hospitalizations in Quebec, including deliveries [14]. Pregnancy complications during prenatal care, delivery, or postpartum are coded following the International Classification of Diseases. Procedures are coded following the Canadian Classification of Diagnostic, Therapeutic and Surgical Procedures and the Canadian Classification of Health Interventions.
Using health insurance numbers, we followed the women prospectively from their first delivery until the time of admission for necrotizing fasciitis. The study ended March 30, 2020, providing up to 31 years of follow-up. We did not include patients who had necrotizing fasciitis before their first delivery, died at delivery, or had missing health insurance numbers (Appendix A: Figure  S1). These patients were not eligible for analysis.
We used diagnostic codes to identify women with these conditions in any pregnancy (Appendix A: Table S1). We expressed pregnancy complications as time-varying covariates to ensure that women were unexposed until the first pregnancy in which a complication appeared [16].

Necrotizing Fasciitis
The outcome was any hospitalization for necrotizing fasciitis during follow-up. Health insurance numbers allowed us to identify admissions anywhere in Quebec between 1989 and 2020. We identified hospitalized patients with diagnostic codes for necrotizing fasciitis and matched them to their delivery hospitalization.
As diabetes frequently clusters with necrotizing fasciitis, we used diagnostic codes from the International Classification of Diseases to determine whether women had coinciding diabetes (Appendix A: Table S1). We thus included both diabetes-related and nondiabetic necrotizing fasciitis.
We had full coverage of necrotizing fasciitis in the population. Because necrotizing fasciitis is life-threaten-ing, patients with this disorder require hospitalization for surgical debridement, monitoring, or critical care. Previous validation studies have shown that outcomes in the data have high sensitivity and specificity [17].
There was little difference in the incidence of necrotizing fasciitis between exposed and unexposed women in the immediate period after pregnancy ( Figure 1). For women with gestational diabetes, preeclampsia, severe maternal morbidity, and preterm birth, the difference in risk of necrotizing fasciitis became more marked 10 to 15 years after delivery. For women with metabolic disorders or prior infectious disease hospitalizations, the difference in risk began to appear 5 years after delivery.
In adjusted regression models, pregnancy complications were more strongly associated with necrotizing fasciitis 5 years or more after delivery ( Figure 2). Cesarean section was associated with 1.59 times (95% CI 1.13-2.24), chorioamnionitis with 1.70 times (95% CI 1.01-2.87), preterm birth with 2.36 times (95% CI 1.55-3.60), low birth weight with 1.90 times (95% CI 1.18-3.08), and neonatal jaundice with 1.79 times (95% CI 1.27-2.52) the risk of necrotizing fasciitis 5 to 14 years after pregnancy. Women with metabolic disorders, immune-related disease, prior infectious disease hospitalization, and kidney disease also had an elevated risk of necrotizing fasciitis 5 to 14 years after delivery. Gestational diabetes, preterm birth, metabolic disorders, prior infectious disease hospitalization, and kidney disease remained associated with necrotizing fasciitis 15 years or more after delivery. In contrast, only cesarean section and metabolic disorders were associated with necrotizing fasciitis within 5 years of delivery. In sensitivity analyses, analysis of characteristics at the first pregnancy led to similar findings.

Data Analysis
We calculated the rate of necrotizing fasciitis per 100,000 person-years and the cumulative incidence at 31 years of follow-up. We used time-varying Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of pregnancy complications with risk of necrotizing fasciitis during follow-up. We adjusted the models for age, substance use disorders, socioeconomic deprivation, place of residence, and time period. The time scale was the number of days since first delivery. We accounted for death as a competing outcome using the Fine and Gray method, and censored women who never developed necrotizing fasciitis by the end of study. We examined the proportionality of hazards using survival curves.
In secondary analyses, we assessed the association between pregnancy characteristics and diabetes-related vs. nondiabetic necrotizing fasciitis. We also determined if the association between pregnancy characteristics and necrotizing fasciitis strengthened over time. To do so, we estimated the risk of necrotizing fasciitis by time interval, including 0-4, 5-14, and ≥15 years after the first delivery.
In sensitivity analyses, we analyzed characteristics at the first pregnancy only, as some women do not have subsequent pregnancies. We analyzed the data in SAS v9.4 (SAS Institute Inc., Cary, NC). As we worked with de-identified data, the University of Montreal Hospital Centre's institutional review board waived ethics review.

RESULTS
The cohort included 1,344,996 women with 23,674,870 person-years of follow-up (Table 1). A total of 420 women developed necrotizing fasciitis, including 269 (64.0%) who required intensive care. Group A Streptococcus was responsible for 151 cases of necrotizing fasciitis (36.0%) and Staphylococcus for 79 cases (18.8%). Diabetes-related necrotizing fasciitis accounted for 83 cases (19.8%). The mean age of women at hospitalization for necrotizing fasciitis was 40.6 years (SD 9.5), and the mean time between delivery and hospitalization was 13.5 years (SD 8.2). Rates of necrotizing fasciitis ranged from 3 to 10 per 100,000 person-years for most pregnancy complications. For women with no pregnancy complication, the rate was 1.1 per 100,000 person-years.
Pregnancy complications were associated with an increased risk of necrotizing fasciitis ( Necrotizing fasciitis is a rare and dangerous infection requiring urgent surgical debridement to prevent mortality [4]. Necrotizing fasciitis is caused by bacteria that penetrate deep fascia after skin trauma, surgery, burns, or other factors compromising the dermal barrier. The extremities are the most common site of infection [4]. There are two types of necrotizing fasciitis: polymicrobial and monomicrobial [18]. Type I, or polymicrobial fasciitis, is caused by aerobic and anaerobic bacteria, and accounts for 80% to 90% of cases [4]. Type II, or monomicrobial fasciitis, is often caused by group A Streptococcus or methicillin-resistant Staphylococcus aureus [18]. In our three decades of follow-up, we found strong associations between gestational diabetes, preeclampsia, preterm birth, severe maternal morbidity, and other pregnancy complications and the subsequent risk of necrotizing fasciitis. Pregnancy complications were more strongly associated with diabetes-related necrotizing fasciitis, although associations were also present with nondiabetic necrotizing fasciitis. Associations strengthened around 5 years after pregnancy and persisted up to 31 years later. The findings suggest that pregnancy characteristics are markers of later onset of metabolic or immunosuppressive disorders that increase the risk of necrotizing fasciitis in women.

Patient characteristic
Hazard ratio (95% confidence interval) a  study, a third of cases involved group A Streptococcus and a fifth involved Staphylococcus. Infection is the most common reason for hospital readmission after pregnancy [19,20]. There is growing evidence that pregnancy complications are associated with severe maternal infections the first year postpartum [7,8]. In a study of 2 million women in the US, postpartum hemorrhage, preterm birth, and cesarean section were associated with two to five times greater odds of readmission for sepsis up to 9 months after pregnancy [7]. A study of 222,751 women found that cesarean delivery was associated with 2.5 times the risk of sepsis or bacteremia 6 weeks postpartum, compared with vaginal delivery [8].
However, risk factors for necrotizing fasciitis are not well understood. Type 2 diabetes is present in up to 60% preeclampsia, and other adverse outcomes all had an elevated risk of necrotizing fasciitis in the long term. Many of these pregnancy outcomes are associated with the development of known risk factors for necrotizing fasciitis, such as type 2 diabetes and obesity. Gestational diabetes is associated with 7 times and preeclampsia with 2 times the risk of developing type 2 diabetes after pregnancy [12,13]. In our data, associations were more pronounced 5 years after delivery, supporting the possibility that pregnancy complications are an early sign of long-term metabolic disorders that increase the risk of necrotizing fasciitis later on. Gestational diabetes and preeclampsia are also associated with cesarean section and preterm delivery [23,26], other complications we found were associated with necrotizing fasciitis.
A related issue is that we could not adjust for all confounders, as necrotizing fasciitis was rare and pregnancy complications were too numerous to include in one time-varying model. Pregnancy complications may be correlated or share metabolic pathways. Preterm birth, low birth weight, preeclampsia, and other pregnancy complications frequently coincide. Metabolic disorders are involved in a range of pregnancy complications, including preeclampsia, gestational diabetes, preterm birth, and cesarean section [27][28][29], all of which were associated with necrotizing fasciitis in our study. Up to 24% of pregnancy complications are attributable to overweight and obesity [27]. Future studies with larger numbers of patients with necrotizing fasciitis will be needed to disentangle the effects of interrelated pregnancy complications.
of cases [4]. Immunocompromised patients are also at greater risk. Smoking, obesity, intravenous drug use, cardiac disease, kidney disease, and age are other risk factors [2][3][4]. In our study, women with metabolic disorders, immune-related disease, prior infectious disease hospitalizations, and kidney disease all had an elevated long-term risk of necrotizing fasciitis. Nevertheless, data suggest that previously healthy people account for around half of cases of necrotizing fasciitis [4]. For this reason, better documentation of risk factors for necrotizing fasciitis is needed. Pregnancy characteristics may be particularly promising because a growing number of studies suggest that adverse pregnancy outcomes predict chronic disease later in life [21][22][23].
While researchers have not yet examined the longterm risk of necrotizing fasciitis after pregnancy, a number of studies have assessed the antepartum and postpartum periods [5]. In a study of 4,060,201 women admitted during pregnancy, 148 had necrotizing fasciitis, including 82.4% that occurred postpartum [5]. Only a third of women with necrotizing fasciitis had a chronic comorbidity. A study of 5048 women with cesarean section identified nine cases of polymicrobial necrotizing fasciitis within 2 weeks of delivery [6]. Necrotizing fasciitis after cesarean section is rare, and most data are limited to case reports of otherwise healthy women following surgical complications [24,25]. Our findings suggest that cesarean delivery is also associated with necrotizing fasciitis after the postpartum period.
In this study, women with gestational diabetes,   Women with complications during pregnancy are considered at risk of cardiovascular disease and encouraged to adopt preventative health behaviors [21][22][23]. However, these benefits could also extend to the prevention of serious infectious diseases, including necrotizing fasciitis. Prevention of harmful infectious diseases may begin early in life for women who experience pregnancy complications.
Nonmetabolic or immune pathways may also be involved, as many women had nondiabetic necrotizing fasciitis in this study. Women with placental disorders, postpartum hemorrhage, severe maternal morbidity, multiple birth, and neonatal jaundice all had elevated risks of nondiabetic necrotizing fasciitis. While some of these pregnancy complications may be linked with immunosuppressive disorders, this pathway is not immediately apparent for conditions such as postpartum hemorrhage and placental disorders. Further research is warranted to identify pathways that may explain the associations.
The risk of necrotizing fasciitis may be modulated by predisposing risk factors such as socioeconomic status or race and ethnicity. We were able to adjust for socioeconomic deprivation but did not have data on race and ethnicity in this study. A 6-year retrospective review of 130 patients from Manitoba found that the incidence of necrotizing fasciitis was higher in the Aboriginal population than other individuals [30]. While there is a paucity of studies on the role of race and ethnicity in necrotizing fasciitis, there is some evidence of an association with outcomes such as sepsis. A study of 10 million patients in the United States found that the incidence of sepsis was higher among non-white patients, and that mortality was greatest for Black men [31]. Although we did not have information on race and ethnicity, Quebec is multicultural, and the results are likely representative of areas with racial diversity.
This study had other limitations. We could not investigate rare pregnancy complications due to the limited number of women with necrotizing fasciitis. We had 80% power to detect an odds ratio of 1.71 and 90% power for an odds ratio of 1.86, assuming a prevalence of 4 pregnancy complications per 100 women, 4 cases of necrotizing fasciitis per 10,000 exposed women, and a 2-tailed α=0.05 [32]. We could not differentiate polymicrobial from monomicrobial fasciitis and lacked information on infection severity. Residual confounding may be present due to underreporting of substance use disorders. Potential confounders such as immunosuppressive drugs were not available. We used hospital data and cannot rule out misclassification of variables due to coding errors. We could not determine the reason for cesarean delivery or the extent to which pregnancy complications predict risk factors in the path to necrotizing fasciitis, although we were able to identify nondiabetic necrotizing fasciitis. The findings apply to a population with publicly funded healthcare, but generalizability to regions with different healthcare delivery models is to be determined.
The overall message conveyed by this study is that gestational diabetes, preeclampsia, and other adverse pregnancy outcomes may be predictors of rare infectious diseases later in life, most likely due to intervening diabetes, obesity, or other immunosuppressive conditions.