Clostridium difficile infection is the most common cause of infectious diarrhea in hospitalized patients and has recently replaced methicillin-resistant Staphylococcus aureus as the primary cause of hospital-acquired infection.1C difficile is a spore-forming Gram-positive bacillus producing heat-labile exotoxins A and B, which are associated with inflammatory fluid secretion and intestinal mucosal damage.2 Clinical manifestations range from a mild watery diarrhea to fulminant colitis and death. Antibiotic use is a risk factor for C difficile infection because antibiotics disrupt normal gut microbia allowing C difficile proliferation.3 Historically, C difficile infection primarily affected the elderly, immunosuppressed, and hospitalized patients.
Recent studies have shown increasing rates of C difficile infection among patients previously thought to be at low risk, including young and healthy peripartum women.4–7 This epidemiologic change is attributed to both a change in antibiotic use as well as the emergence of a hypervirulent and hyperepidemic BI/NAP1/027 C difficile strain.8,9 The first cases of obstetric C difficile infection were reported in 1985 (Duff P. Pseudomembranous enterocolitis after cesarean delivery [letter]. Am J Obstet Gynecol 1985;153:926.).10,11 In 2005, a report identified 10 C difficile infection cases in the peripartum population across four American states.4 In 2011, Unger et al5 described an outbreak of 20 cases of C difficile infection on the obstetric unit of a tertiary teaching hospital from April 2006 to June 2007. Kuntz et al6 found that in the United States, it appears that the incidence and possible severity of obstetric C difficile infection are increasing.
The aim of this study was to evaluate the risk factors, incidence, and morbidity associated with the diagnosis of C difficile infection in an obstetric population.
MATERIALS AND METHODS
We performed a retrospective cohort study using the data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database of 1999 to 2013.12 This database, which is maintained by the Agency for Healthcare Research and Quality, is composed of information on hospital inpatient stays submitted by participating hospitals throughout the United States. It is the largest database of its kind. Each year, the Healthcare Cost and Utilization Project Nationwide Inpatient Sample provides data relating to 47 million inpatient stays, approximating a 20% stratified sample of all U.S. hospitals. With records from approximately 1,000 U.S. hospitals, the data are weighted to represent inpatient stays from community, academic, urban, rural, private, and public hospitals from across the country to allow for the presentation of national estimates. Diagnoses in the Healthcare Cost and Utilization Project records are based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM).
Our cohort was identified by obtaining all records containing birth-related diagnostic codes ICD-9-CM codes v27.x or 65x.x or 66x.x. Within this subset, all women with C difficile infection were identified using ICD-9-CM diagnostic code 008.45. The remaining deliveries were categorized as non–C difficile infection births and constitute the comparison group for our analyses. It should be noted that other studies based on the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database have also used ICD-9-CM code 008.45 to identify C difficile infection cases.13–15 Furthermore, because hospital discharge is the unit of analysis, not the patient, it is possible for a patient who gave birth multiple times within our study period of interest to be considered more than once within our analyses. We acknowledge that this may lead to underestimation of CIs.
Logistic regression models were used to compare baseline demographic and clinical characteristics of women affected by C difficile infection compared with those without C difficile infection. All models were adjusted for the following variables: age, race, income quartiles, insurance type (Medicaid, private, other), multiple gestation, gestational diabetes, smoking status, Crohn's disease, ulcerative colitis, long-term use of antibiotics, hospital location (rural, urban teaching, urban nonteaching), and hospital bed size (small, medium, large).
We used SAS 9.1 for all analyses. Because this study used publicly available data, the Jewish General Hospital Medical/Biomedical Research Ethics Committee has deemed this study to be exempt from research ethics board approval in accordance with the 2010 Tri-Council Policy statement.
Of the total 13,881,592 births in our cohort, we identified 2,757 (0.02%) admissions for delivery complicated by a diagnosis of C difficile infection. This represented an average of almost 20 admissions of pregnant women with C difficile infection per 100,000 deliveries per year (95% CI 19.13–20.62). The rate of delivery admissions complicated by a diagnosis of C difficile infection doubled over a 15-year period, from 15 admissions per 100,000 deliveries (95% CI 11.87–16.96) in 1999 to 30 in 2013 (95% CI 24.42–31.78; P<.001, R2 0.95; Fig. 1).
Older women, smokers, and women with multifetal pregnancies were at increased risk for the diagnosis C difficile infection. Women on long-term antibiotics were at an increased risk of being diagnosed with C difficile infection as were women with a diagnosis of Crohn's and ulcerative colitis. Infections such as pyelonephritis and perineal or cesarean wound infections were also associated with a higher risk for the diagnosis of C difficile infection. In particular, inpatients with pneumonia in pregnancy were 67 times more likely to be diagnosed with C difficile infection (Table 1).
Among pregnant women admitted for delivery and diagnosed with C difficile infection, we found that among other major complications, venous thromboembolism occurred in 38.4 (31.5–46.5) per 1,000 women, paralytic ileus occurred in 58.0 (49.4–67.8) per 1,000 women, sepsis occurred in 46.4 (38.7–55.2) per 1,000 women, and death occurred in 8.0 (5.0–12.1) per 1,000 women, all far more commonly than in women without a diagnosis of C difficile infection in pregnancy (Table 2).
We found a significant increase in obstetric C difficile infection diagnosis over the past 15 years, which confirms the earlier trend observed by Kuntz et al.6 Antibiotic use is the most widely recognized and modifiable risk factor for C difficile infection.16,17 We observed that pregnant women on long-term antibiotics and those likely to receive antibiotic therapy such as women with pyelonephritis, wound infection, and pneumonia were at increased risk of being diagnosed with C difficile infection. Note, the ICD-9-CM V58.62 code used to identify patients on “long-term (current)” antibiotics does not have a specific definition for “long term.” First-trimester use of prescription medication increased by greater than 60% in the past three decades.18 Amoxicillin is the most commonly prescribed drug and eight of the top 20 drugs prescribed in pregnancy are antibiotics.18 An estimated 50% of women are exposed to antibiotics during pregnancy.5 Obstetric care providers should be aware of the potential for C difficile infection and maintain a high degree of suspicion in patients presenting with diarrheal illness postantibiotic use.
Historically, pregnant women were considered at low risk for C difficile infection given their young age and overall healthy state. However, physiologic and immunologic changes of normal pregnancy may place pregnant women at high risk for C difficile infection.7 The adaptive “Th2 phenomena,” which ultimately diminishes rejection of the fetus and miscarriage,19 also reduces the immunoglobulin G antibodies against toxin A and B largely produced under the Th1 system, thus rendering pregnant women more vulnerable to C difficile infection. Furthermore, previous reports suggest that pregnant women tend to have a more severe course of C difficile infection than nonpregnant women.4,20
We observed that women with inflammatory bowel disease had a greater likelihood of C difficile infection diagnosis, which may be attributed to inadequate inflammatory response by the weakened intestinal lymphoepithelium.21 Immunomodulating drugs used for inflammatory bowel disease may also contribute to C difficile infection risk by altering mucosal inflammatory responses.21 Alternatively, this may also reflect a heightened surveillance among women with inflammatory bowel disease.
In nonpregnant women, elevated mortality and morbidity is attributed to the emergence of the hypervirulent NAP1 strain.22 Overall, in the United States, the C difficile infection–attributable mortality rate had risen from 1.5% before 2000 to 4.5–5.7% in the current endemic period.1 The NAP1 strain causing severe disease among high-risk populations is likely also responsible for the increasing frequency and severity of cases in pregnant women.4Clostridium difficile infection is often underdiagnosed as a result of low clinical suspicion and suboptimal laboratory diagnostic methods.23 Testing for C difficile infection should be performed on all patients with clinically significant diarrhea, defined as three or more loose stools per day for at least 1–2 days.24,25 Diagnosis is often made by a combination of two reference methods, including a cytotoxigenic culture, which detects the presence of C difficile bacteria, and a cytotoxin assay, which detects preformed toxins in the stool.23,26
Current treatments for C difficile infection include metronidazole for milder cases, vancomycin for severe C difficile infection, and dual therapy for recurrent or high-risk situations.25,27 Moreover, a recent case report describes obstetric C difficile infection refractory to antibiotics that was successfully treated with fecal microbiota transplantation.28 Although the use of fecal microbiota transplant is recommended in individuals who have had two or more recurrences of C difficile infection with failure of vancomycin, two or more episodes of C difficile infection with one resulting in hospitalization, or refractory C difficile infection,27 further large studies are warranted to determine the safety and efficacy in pregnant women.28 Transmission can be prevented by patient isolation and strict hand hygiene, including gloves and gowns, for all health care workers and visitors of patients with known or suspected C difficile infection.27
Our study is limited by the information available in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. For instance, we were unable to determine the timeline for the C difficile infection diagnosis in relation to delivery. It is unclear how often C difficile infection was the initial cause of admission compared with an opportunistic infection occurring when hospitalization for another indication. Also, information about medication use was not available; hence, we were unable to identify the specific type of antibiotic exposure. Furthermore, we could not characterize duration of antibiotic use beyond “long-term (current)” use as a result of a lack of detail in ICD-9-CM code V58.62. Also, the method of C difficile infection detection, which was unavailable, may have changed over time. Data pertaining to NAP1 incidence and recurrent C difficile infection were also absent from the database. Furthermore, the obstetric C difficile infection incidence reported here is likely underestimated because we could not account for patients treated without admission to the hospital. Outpatient cases likely represent milder presentations and could change the overall clinical picture of severity.
The rate of diagnosed obstetric C difficile infection has doubled over the past 15 years in the United States. Pregnant women admitted and diagnosed with C difficile infection are at significantly increased risk of sepsis and death. Clinicians must therefore have a high index of suspicion for C difficile infection and use antibiotics only when required in pregnant patients. Further studies comparing C difficile infection in pregnancy with age-matched nonpregnant women without infection would help us better understand the unique consequences of obstetric C difficile infection.
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