clostridium difficile–associated diarrhea: an emerging threat to pregnant women

6
OBSTETRICS Clostridium difficile–associated diarrhea: an emerging threat to pregnant women Nadine G. Rouphael, MD; Judith A. O’Donnell, MD; Julu Bhatnagar, PhD; Felicia Lewis, MD; Philip M. Polgreen, MD; Susan Beekmann, RN, MPH; Jeannette Guarner, MD; George E. Killgore, DrPH; Becky Coffman, RN, MPH; Jennifer Campbell, MD; Sherif R. Zaki, MD, PhD; L. Clifford McDonald, MD OBJECTIVE: To estimate if Clostridium difficile-associated disease (CDAD) is increasing in peripartum women. STUDY DESIGN: Peripartum CDAD was assessed through 1) passive surveillance collecting clinical and pathology data on severe cases and 2) survey among infectious disease consultants (ICDs) in the Emerging Infections Network. RESULTS: Ten severe cases were collected; most had associated anti- biotic use. Seven women were either admitted to the ICU or underwent colectomy. Three infants were stillborn, and 3 women died. The epi- demic Clostridium difficile strain was found in 2 cases. Among 798 ICDs, 419 (52%) participated in the survey. Thirty-seven respondents (9%) recalled 55 cases, mostly in the postpartum period with 21 com- plications, mainly due to relapse. CONCLUSION: Severe CDAD may be increasing in peripartum women. Clinicians should have a low threshold for testing, be aware of the potential for severe outcomes, and take steps to reduce both the risk of disease and resultant complications. Key words: case series, Clostridium difficile, pregnancy, survey Cite this article as: Rouphael NG, O’Donnell JA, Bhatnagar J, et al. Clostridium difficile–associated diarrhea: an emerging threat to pregnant women. Am J Obstet Gynecol 2008;198:635.e1-635.e6. I n the US, Clostridium difficile is the most common cause of infectious di- arrhea in hospitalized patients, usually affecting older patients with chronic un- derlying illness and recent antimicrobial exposure. There has been a recent change in the epidemiology of Clostrid- ium difficile–associated disease (CDAD) with an increase in the incidence and se- verity. Data collected on national esti- mates of US short-stay hospital dis charges revealed a doubling of CDAD discharge diagnoses from 2000 through 2003. 1 At a tertiary care center in Pitts- burgh, the proportion of CDAD cases with life threatening disease increased from 0% in 1990 to 3.2% in 2000 with 44 colectomies and 20 deaths reported. 2 Much, if not all, of this increased inci- dence and severity may be due to the emergence of a hypervirulent strain of C difficile. 3 Largely due to their young age and overall good health, pregnant women have historically been at low risk for de- veloping CDAD. In a retrospective study of 74,120 admissions to an obstetrics and gynecology service over 10 years, only 18 women (0.02%) developed CDAD. 4 However, a Morbidity and Mortality Weekly Report (MMWR) reported 10 cases of peripartum disease from 4 states; among these women, 40% required hos- pitalization, 50% experienced relapse, and 1 died. 5 It is possible that, nation- wide, pregnant women are at increased risk for severe C difficile infection due to the epidemic strain. To assess this hy- pothesis, we described the clinical and pathologic features of recently reported cases and surveyed infectious diseases consultants (IDCs) about the frequency and severity of peripartum CDAD in their practice. MATERIALS AND METHODS Case series From 2005 through 2006, 10 women with severe CDAD during their pregnancy or within 4 weeks of delivery were identified From the Division of Bacterial Diseases (Dr Rouphael), Infectious Diseases Pathology Activity (Drs Bhatnagar and Zaki), the Epidemic Intelligence Service Field Assignments Branch, Office of Workforce and Career Development (Dr Lewis), and the Division of Healthcare Quality Promotion (Drs Killgore and McDonald), Centers for Disease Control and Prevention, Atlanta, GA; the Division of Infectious Diseases (Dr O’Donnell) and the Department of Obstetrics and Gynecology (Dr Campbell), Drexel University College of Medicine, Philadelphia, PA; the Infectious Diseases Society of America Emerging Infections Network, Iowa City, IA (Dr Polgreen and Ms Beekmann); the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA (Dr Guarner); the Oklahoma State Department of Health, Oklahoma City, OK (Ms Coffman); and the Philadelphia Department of Public Health, Philadelphia, PA (Dr Lewis). Received July 18, 2007; revised Oct. 22, 2007; accepted Jan. 31, 2008. Reprints: L. Clifford McDonald, MD, CDC. [email protected]. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. 0002-9378/$34.00 • © 2008 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2008.01.062 For Editors’ Commentary, see Table of Contents Research www. AJOG.org JUNE 2008 American Journal of Obstetrics & Gynecology 635.e1

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Page 1: Clostridium difficile–associated diarrhea: an emerging threat to pregnant women

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BSTETRICS

lostridium difficile–associated diarrhea:n emerging threat to pregnant women

adine G. Rouphael, MD; Judith A. O’Donnell, MD; Julu Bhatnagar, PhD; Felicia Lewis, MD; Philip M. Polgreen, MD;usan Beekmann, RN, MPH; Jeannette Guarner, MD; George E. Killgore, DrPH; Becky Coffman, RN, MPH;ennifer Campbell, MD; Sherif R. Zaki, MD, PhD; L. Clifford McDonald, MD

BJECTIVE: To estimate if Clostridium difficile-associated diseaseCDAD) is increasing in peripartum women.

TUDY DESIGN: Peripartum CDAD was assessed through 1) passiveurveillance collecting clinical and pathology data on severe cases and) survey among infectious disease consultants (ICDs) in the Emergingnfections Network.

ESULTS: Ten severe cases were collected; most had associated anti-iotic use. Seven women were either admitted to the ICU or underwent

emic Clostridium difficile strain was found in 2 cases. Among 798CDs, 419 (52%) participated in the survey. Thirty-seven respondents9%) recalled 55 cases, mostly in the postpartum period with 21 com-lications, mainly due to relapse.

ONCLUSION: Severe CDAD may be increasing in peripartum women.linicians should have a low threshold for testing, be aware of theotential for severe outcomes, and take steps to reduce both the risk ofisease and resultant complications.

olectomy. Three infants were stillborn, and 3 women died. The epi- Key words: case series, Clostridium difficile, pregnancy, survey

ite this article as: Rouphael NG, O’Donnell JA, Bhatnagar J, et al. Clostridium difficile–associated diarrhea: an emerging threat to pregnant women. Am J Obstetynecol 2008;198:635.e1-635.e6.

n the US, Clostridium difficile is themost common cause of infectious di-

rrhea in hospitalized patients, usuallyffecting older patients with chronic un-erlying illness and recent antimicrobialxposure. There has been a recenthange in the epidemiology of Clostrid-um difficile–associated disease (CDAD)ith an increase in the incidence and se-erity. Data collected on national esti-ates of US short-stay hospital dis

charges revealed a doubling of CDADdischarge diagnoses from 2000 through2003.1 At a tertiary care center in Pitts-burgh, the proportion of CDAD caseswith life threatening disease increasedfrom 0% in 1990 to 3.2% in 2000 with 44colectomies and 20 deaths reported.2

Much, if not all, of this increased inci-dence and severity may be due to the

emergence of a hypervirulent strain of Cdifficile.3

Largely due to their young age andoverall good health, pregnant womenhave historically been at low risk for de-veloping CDAD. In a retrospective studyof 74,120 admissions to an obstetrics andgynecology service over 10 years, only 18women (0.02%) developed CDAD.4

However, a Morbidity and MortalityWeekly Report (MMWR) reported 10cases of peripartum disease from 4 states;among these women, 40% required hos-pitalization, 50% experienced relapse,and 1 died.5 It is possible that, nation-wide, pregnant women are at increasedrisk for severe C difficile infection due tothe epidemic strain. To assess this hy-pothesis, we described the clinical andpathologic features of recently reportedcases and surveyed infectious diseasesconsultants (IDCs) about the frequencyand severity of peripartum CDAD intheir practice.

MATERIALS AND METHODSCase seriesFrom 2005 through 2006, 10 women withsevere CDAD during their pregnancy or

rom the Division of Bacterial Diseases (Dr Rouphael), Infectious Diseases Pathologyctivity (Drs Bhatnagar and Zaki), the Epidemic Intelligence Service Field Assignmentsranch, Office of Workforce and Career Development (Dr Lewis), and the Division ofealthcare Quality Promotion (Drs Killgore and McDonald), Centers for Disease Control

nd Prevention, Atlanta, GA; the Division of Infectious Diseases (Dr O’Donnell) and theepartment of Obstetrics and Gynecology (Dr Campbell), Drexel University College ofedicine, Philadelphia, PA; the Infectious Diseases Society of America Emerging Infectionsetwork, Iowa City, IA (Dr Polgreen and Ms Beekmann); the Department of Pathology andaboratory Medicine, Emory University School of Medicine, Atlanta, GA (Dr Guarner); theklahoma State Department of Health, Oklahoma City, OK (Ms Coffman); and thehiladelphia Department of Public Health, Philadelphia, PA (Dr Lewis).

eceived July 18, 2007; revised Oct. 22, 2007; accepted Jan. 31, 2008.

eprints: L. Clifford McDonald, MD, CDC. [email protected].

he findings and conclusions in this report are those of the authors and do not necessarilyepresent the views of the Centers for Disease Control and Prevention.

002-9378/$34.00 • © 2008 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2008.01.062

For Editors’ Commentary, see Table of Contents

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hrough passive reporting. CDAD wasonsidered severe if it resulted in hospital-zation, intensive care unit (ICU) admis-ion, colectomy, or death.

Five women were reported to the Cen-ers for Disease Control and PreventionCDC) either directly by the patient her-elf, her treating physician, or by hospitalersonnel through local and state healthepartments. These cases were reported

rom 4 different states (PennsylvaniaPA] published in MMWR,5 OklahomaOK], Georgia [GA], and CaliforniaCA]). An additional 4 cases were re-orted from the obstetrics and gynecol-gy service at a tertiary care center inennsylvania and the last case was fromhio (OH) and recently published in the

iterature.6

A standardized form was used to col-ect demographic, clinical, laboratory,

icrobiology, radiology, and pathologyata from cases. The diagnosis of CDADas established if a patient presentedith consistent clinical symptoms or

igns and either a premortem stool spec-men positive for C difficile toxins A/B vianzyme-linked immunosorbent assayELISA) or the presence of pseudomem-ranes observed during endoscopy or insurgical or autopsy specimen. Only 1

tool specimen was available for C diffi-ile culture.

aboratory investigationsvailable surgical and autopsy tissues werevaluated at the CDC. Immunohisto-hemical staining was performed using aolyclonal anti-Clostridium spp. (Biode-ign, Saco, ME) antibody known to cross-eact with multiple Clostridium species.7

NA was extracted from formalin-fixedissues using the QIAamp DNA Mini KitQIAGEN, Valencia, CA) and C difficilepecific PCR assay was performed usingreviously described primers8 and theigh Fidelity PCR kit (Roche Diagnostics,

ndianapolis, IN). Amplified PCR prod-cts were sequenced on a CEQ 2000 XLequencer (Beckman Coulter, Fullerton,A). A search for homologies to known

equences was done using the Basic Locallignment Search Tool (BLAST) atttp://www.ncbi.nlm.nih.gov/BLAST/.pecimens that were positive for tcdB were

urther evaluated for both the presence of s

35.e2 American Journal of Obstetrics & Gynecolo

inary toxin by PCR amplification of cdtBnd for deletions in the putative negativeoxin-regulatory gene, tcdC, using previ-usly described methods.3

urveyhe Emerging Infections Network (EIN)

s a provider-based sentinel network op-rated by the Infectious Diseases Societyf America (IDSA). It includes over 900linicians worldwide, with the majorityesiding in the US. The IDSA EIN is de-igned to provide a rapid assessment ofDCs’ perceptions regarding diseasemergence and trends. In April 2006, a-question survey was distributed to theajority of IDSA EIN members in theS and Canada via e-mail or facsimile.he survey inquired about the members’xperience with CDAD in peripartumomen in the previous 6 months, partic-larly in regards to the relative frequencyf cases, relapses, and severity of disease.embers were asked if they had “seen”

r were “aware of ” cases of CDAD, theiming of these cases in relation to deliv-ry, and complications related to thesevents. Complications were defined aselapse, development of toxic megacolonith or without the need for colectomy,

olonic perforation, and death. Nonre-pondents received a second and a third

ailing 7 and 14 days later, respectively.This activity was determined by CDC

ot to be human subject research; hu-an subjects regulations do not apply.

ESULTSase seriesen women with severe CDAD are de-

cribed (PA-1 to 5, OK-1, 2, GA, CA,H) (Table 1). The mean age was 28.2

range 18-40) years. Four women werehite, 4 were African American, 1 wasispanic, and 1 was from the Marshall

slands. Seven had prior pregnanciesexcept for PA-3, OK-2, and OH). Only 1atient was HIV positive (PA-4); how-ver, her CD4 cell count was 700 cells/m3, her viral load was undetectable,

nd she had no history of AIDS. Threeatients had a prior history of hospital-

zation and 9 had prior antibiotic use inhe 3 months preceding their admissionor CDAD. Patients developed CDAD

ymptoms 3 to 60 days after antibiotic t

gy JUNE 2008

dministration with a median of 5 days.one of the patients for whom informa-

ion was available (n � 6) had receivedroton pump inhibitor (PPI) therapy.ix cases occurred prior to delivery and 3ut of 4 postpartum cases occurredithin 1 week of delivery.Clinical symptoms included diarrhea

n � 7), abdominal pain (n � 9) andistension (n � 6), vomiting (n � 1),nd fever (temperature � 101°F) (n �). Available white blood cell counts (n

9) were always elevated and rangedrom 11,000 to 72,000 cells/�L (OK-2).erum creatinine was elevated in 3 pa-ients and ranged from 0.5-5.4 mg/dLnd albumin was generally low (1-2.8/dL). All patients who had available im-ging results (n � 8) had abnormal find-ngs on roentgenographic imaging ofidneys, ureters, bladder (KUB), com-uted tomography (CT), or magneticesonance imaging (MRI). The mostommon finding on imaging was radio-raphic evidence of pancolitis with di-ated loops and thickening (n � 8); alsooted were the presence of air-fluid lev-ls (n � 2), ascites (n � 2), and pneuma-osis (n � 1). Diagnosis of CDAD wasstablished by a positive test for toxin/B in 9 patients and/or the presence ofseudomembranes in 7 patients. Only 1atient (PA-3) had a stool sample sent

or culture and was positive for the re-ently described epidemic strain of Cifficile.3

Oral vancomycin with or without met-onidazole was given to 8 patients for a me-ian of 14 (range 14-30) days. No patienteceived probiotics or intravenous immu-oglobulins. One patient died before re-eiving any treatment and the diagnosis ofDAD was made at autopsy (OK-1). Me-ian hospital stay was 15 (range 2-80) days.ix of the 10 patients required admission tohe ICU and 5 underwent a subtotal colec-omy. Six patients developed toxic mega-olon, 3 had sepsis, 3 had renal failure, andhad disseminated intravascular coagula-

ion (DIC). Two patients relapsed. Deathccurred in 3 patients and there were 3tillbirths: 1 in a woman with a singletonregnancy (GA) and 2 in a woman with

wins (PA-1).
Page 3: Clostridium difficile–associated diarrhea: an emerging threat to pregnant women

TABLE 1Characteristics of patients with severe Clostridium difficile–associated diarrhea among 10 peripartum women

Case AgePriorhospitalization Prior antimicrobial use CDAD timing CDAD diagnosis Treatment

HospitalLOS Complications

Mother’soutcome

Baby’soutcome

PA-1 31 None TMP/SMX (urinary tract infection) Antepartum 16 weeks ELISAa

pseudomembranesMetronidazolevancomycincholestyramine

26 days ShockARDStoxic megacoloncolectomy

Death Death (twins)

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

PA-2 27 Yes Amoxicillin-clavulanatemetronidazole (C-section)

Postpartum 3 weeks ELISAa Vancomycin 4 days None Alive Alivefull term

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

PA-3 18 None Oral metronidazole (bacterial vaginosistreatment)

Antepartum 28 weeks ELISAa

pseudomembranesstool culture

Metronidazolevancomycin

15 days Sepsis Alive Alivefull term

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

PA-4 39 None Oral clindamycin (bacterial vaginosistreatment)

Antepartum 25 weeks ELISAa Vancomycin 15 days Relapse Alive Alive

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

PA-5 40 None Yes—unknown agent(cholecystectomy prophylaxis)

Antepartum 12 weeks ELISAa Metronidazolevancomycin

2 days None Alive Unknown

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

OK-1 22 None Clindamycin (C-section) Postpartum � 1week

Pseudomembranes None 7 days Toxic megacolonsepsisrenal failureDIC

Death Alivefull term

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

OK-2 21 Yes Azithromycin 1st and 3rd generationcephalosporin, amoxicillin(C-section, GBS prophylaxis)

Postpartum � 1week

ELISAa

pseudomembranesVancomycinmetronidazole

17 days Toxic megacoloncolectomy

Death Alive

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

GA 20 None None Antepartum 22 weeks ELISAa

pseudomembranesIHCb

Vancomycinmetronidazole

15 days Toxic megacoloncolectomy

Alive Death

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

CA 40 None 1st generation ephalosporin,erythromycin (C-section, prophylaxisafter amniotic fluid loss)

Antepartum 31 weeks ELISAa

pseudomembranesIHCb

Vancomycinmetronidazole

80 days Septic shockrenal failurerespiratory failureDICtoxic megacoloncolectomyrelapse

Alive Alivepreterm

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

OH 24 Yes(C-section)

1st generation cephalosporin,amoxicillin-clavulanate (C-section,treatment of endometritis andcellulitis)

Postpartum � 1week

ELISAa

pseudomembranesMetronidazole 12 days Toxic megacolon

colectomyAlive Alive

............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

ARDS, adult respiratory distress syndrome; CA, California; DIC, disseminated intravascular coagulation; GA, Georgia; GBS, group B streptococcus; LOS, length of stay; OH, Ohio; OK, Oklahoma; PA, Pennsylvania; TMP/SMX, trimethoprim/sulfamethoxazole.a ELISA, positive C difficile toxins A and/or B via enzyme-linked immunosorbent assay.b IHC, positive immunohistochemistry using polyclonal anti-Clostridium spp.

Rouphael. Clostridium difficile–associated diarrhea. Am J Obstet Gynecol 2008.

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aboratory investigationsive formalin-fixed colonic tissues ob-ained either at autopsy (OK-1) or dur-ng subtotal colectomy (PA-1, GA, CA,

H) were available and all showedseudomembranes. The IHC for Clos-ridium spp. and C difficile tcdB gene am-lification was positive in 2 of these casesGA, CA). Sequence analysis of bothositive amplicons confirmed the pres-nce of C difficile. One of these 2 casesCA) also tested positive for the presencef the binary toxin gene, cdtB, and an 18-ase pair deletion in tcdC, suggesting in-ection with the recently described C dif-cile epidemic strain. A 6th case (PA-3)ad the epidemic strain of C difficile re-overed from stool culture.

urveyhe IDSA EIN questionnaire yielded re-

ponses from 419 out of 798 (52.5%) phy-icians surveyed. Thirty-seven (8.8%) re-pondents had either “seen” or wereaware of ” a total of 55 cases of peripartumDAD (Table 2). Nineteen respondents

eported they were “aware of ” 27 peripar-um CDAD cases and 18 had “seen” 28

TABLE 2Infectious Diseases Society of AmeEmerging Infections Network (EIN)

Num“se

Cases of peripartum CDAD 28...................................................................................................................

Antepartum 6...................................................................................................................

First trimester 1...................................................................................................................

Second trimester 2...................................................................................................................

Third trimester 3...................................................................................................................

Postpartum 20...................................................................................................................

� 1 week after delivery 3...................................................................................................................

� 1 week after delivery 11...................................................................................................................

Number of complications 7...................................................................................................................

Relapse 3...................................................................................................................

Toxic megacolon 2...................................................................................................................

Colectomy 1...................................................................................................................

Colonic perforation 0...................................................................................................................

Fetal loss 1...................................................................................................................

Death 0Rouphael. Clostridium difficile–associated diarrhea. Am J

ases. One provider might have cared for e

35.e4 American Journal of Obstetrics & Gynecolo

ore than 1 peripartum CDAD case: 11, 4,nd 3 IDCs had seen 1, 2, and 3 cases, re-pectively. Also, 1 or several providersould have been “aware of ” the same peri-artum CDAD case “seen” by anotherrovider. The geographic distribution ofll respondents and reported cases ishown in the Figure. Among 49 of the 55ases for which information was available,8 (37%) developed antepartum disease,istributed among all 3 trimesters; 3163%) developed CDAD postpartum,sually greater than 1 week after delivery.wenty-one (43%) complications were re-orted, including 10 relapses and 5 cases ofoxic megacolon. One patient (GA), as de-cribed above, required colectomy and hadetal loss. This patient was reported asseen” by 1 respondent and made “awaref ” by 2 other respondents. No deathsere reported through the IDSA EIN

urvey.

OMMENTistorically, peripartum CDAD has been

onsidered an unusual occurrence andhen present, has generally been mild dis-

a (IDSA)/rvey resultsr of cases Number of cases

“aware of”

27..................................................................................................................

12..................................................................................................................

2..................................................................................................................

4..................................................................................................................

4..................................................................................................................

11..................................................................................................................

4..................................................................................................................

5..................................................................................................................

14..................................................................................................................

7..................................................................................................................

3..................................................................................................................

2..................................................................................................................

0..................................................................................................................

2..................................................................................................................

0tet Gynecol 2008.

ase treated in the outpatient setting. How- r

gy JUNE 2008

ver, in 2005, a MMWR5 raised concernbout a possible increase in both the fre-uency and severity of CDAD in pregnantomen. Most patients in our case-seriesere previously healthy, young, immuno-

ompetent women, with no or limitedrior hospitalization; yet they suffered se-ere complications, including ICU admis-ion, colectomy, death, and fetal loss re-ated to CDAD.

CDAD is not a reportable disease. Thus,o determine how widespread the problemf peripartum CDAD is, we surveyed a

arge sentinel network of IDCs. In the cur-ent study, 8.8% of IDCs surveyed in theS and Canada stated that they had either

een or were aware of CDAD cases in preg-ant women over a 6-month period. Al-

hough this remains a small fraction of allDCs, they reported 55 CDAD cases, someith severe complications, including 10

pisodes of relapse and 5 instances of toxicegacolon. The findings of the survey

ighlight the need to take CDAD seriouslyn this particular population and to raisehe level of concern and vigilance amonghysicians.Although our study cannot determinehether peripartum CDAD is increasing

n frequency or is definitively associatedith higher morbidity and mortality,

here are epidemiological and patho-hysiological explanations as to why thisould be a plausible concern. There is re-ent evidence that CDAD severity andrequency may be increasing not onlyn high-risk populations (eg, hospital-zed, immunocompromised, or elderlyatients) but also among younger andealthier patients from the community.5

oreover, community-associated CDADay be less frequently associated with

ntimicrobial exposure and more fre-uently associated with the use of gastriccid-suppressing medications, namelyroton pump inhibitors (PPI). Ourtudy is consistent with these reports inhat 7 of 10 patients in our series had ei-her no or only limited prior hospitaliza-ion. However, we did not find strong ev-dence of CDAD without precedingntibiotic use; 9 of our 10 patients hadome prior antimicrobial exposure. Re-ponsible agents were from a varietyf antimicrobial classes, including met-

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ine treatment of CDAD, and clindamy-in, an antimicrobial notorious for its as-ociation with CDAD. Even a single dosef an antimicrobial such as a beta lactamnd cephalosporin given prior to cesar-an section for the prevention of group Btreptococcus disease, or for asymptom-tic bacteriuria, may result inDAD.10,11 These findings underscore

he fact that any antimicrobial givenven once can predispose a patient toDAD by disrupting the normal colonicora. PPI use was not documented inny of the patients in our case series. Theack of association between the use of PPInd CDAD in our study could be ex-lained by the small number of patients;owever, other studies suggest that theole of these agents in the developmentf CDAD remains controversial.12

The recent change in the epidemiologyf CDAD, and its possible emergence inregnant women, could be explained bydditional factors. One concern is theidespread promotion and use of alco-ol-based hand sanitizers used in house-olds as well as in the outpatient and in-atient settings and their relative

nability to eradicate C difficile spores.owever, it is becoming clear that the

FIGUREGeographic distribution of pregnancyby IDSA/EIN survey respondents by U

Respondents: 35Seen/Aware of: 0

espondents: 59een: 4ware of: 0

Respondents: 23Seen: 1Aware of: 0

RespondSeen: 1Aware o

CanadaRespondents: 5Seen/Aware of: 0

ouphael. Clostridium difficile–associated diarrhea. Am J Ob

ncreased use of alcohol-based hand fi

anitizers do not have an important rolen increasing CDAD rates.13 Of muchreater concern is the emergence of aew, hypervirulent epidemic strainnown variously by its designations oforth American Pulsed-Field type 1

NAP1), restriction enzyme analysis typeBI,” or PCR ribotype 027.3 This strain isapable of producing 16- and 23-foldore toxins A and B, respectively, in

itro.14 The strain carries both an 18-ase pair (bp) and a point deletion in autative negative toxin-regulatory gene,

cdC, and an extra toxin, known as bi-ary toxin. It is thought that deletions in

cdC could have a role in increased toxinroduction and virulence. Binary toxin

s related to iota toxin in Clostridiumerfringens and its role is not wellnderstood.A major challenge in describing the

hanging epidemiology of CDAD haseen the lack of available C difficile stoolulture isolates from patients becauseearly all hospital laboratories rely ontool toxin assays (usually enzyme im-

unoassays) for the diagnosis. Withouthe actual isolate, further characteriza-ion of the organism is impossible.herefore, we utilized IHC of formalin-

ssociated CDAD cases reportedConsensus Bureau Division, 2006

Respondents: 20Seen/Aware of: 0

Respondents: 85Seen: 4Aware of: 6

27

Respondents: 58Seen: 5Aware of: 7

Respondents: 66Seen: 3Aware of: 1

Respondents: 41Seen: 0Aware of: 4

Gynecol 2008.

xed colonic tissues and nucleic acid am- c

JUNE 2008 Americ

lification of C. difficile-specific DNA.e were able to confirm the presence of

he 18-bp deletion in tcdC and binaryoxin (via presence of cdtB) in one pa-ient (CA case). This patient was mostikely infected with the NAP1/BI/027train. We believe our use of these meth-ds on formalin fixed tissue is unique inot only serving to confirm the role of

he C difficile organism, but also in deter-ining the likely infecting strain. None-

heless, the need to better describe thenfolding epidemiology of CDAD is alear and strong indicator for perform-ng stool cultures in cases of unusuallyevere disease or during outbreaks.

The pathophysiology of CDAD inregnancy remains poorly understood.yne et al demonstrated that anti-toxinIgG confer protection against initial

DAD attacks as well as relapses.15,16 Al-hough antibody production is generallyncreased during pregnancy, this pro-uction may not be specific or protective

n severe CDAD cases. During preg-ancy, particularly in the third trimester,

ype 1/proinflammatory cytokine pro-uction and cellular immunity are sup-ressed with a shift towards a Th2 re-ponse.17 This is due in part to anlevation in cortisol, estrogen, and pro-esterone levels, and at high levels, theseormones tend to have an anti-inflam-atory effect. In animal models, interac-

ions between C difficile toxin and hor-ones may in part explain disease

usceptibility and outcome of peripar-um CDAD.18 In vivo studies are neededo better understand these interactions.

The recent changes in the epidemiol-gy of CDAD may indicate a need for ahange in treatment approach. Oral van-omycin is the only FDA-approved med-cation for the treatment of CDAD andan be used in pregnancy; however, itsigh cost and the emergence of vanco-ycin resistance in other organisms,

articularly enterococci, have madeetronidazole the first line drug for

reating CDAD.19 Recent reports raiseoncern about the use of metronidazolelone in severe CDAD20,21 and suggestancomycin may be more appropriate asfirst line therapy. Most of the patients

n our case series were treated with a

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ents:

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ombination therapy of oral vancomy-

an Journal of Obstetrics & Gynecology 635.e5

Page 6: Clostridium difficile–associated diarrhea: an emerging threat to pregnant women

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6

in and metronidazole although therere no data to support this approach.ew therapeutic modalities are now

vailable including new antimicrobials,oxin-binding products, and active andassive immunization.22 Their role in se-ere CDAD and their safety in pregnancyre still unclear. Most importantly, theptimal management of CDAD in preg-ant women must include a low thresh-ld for testing, early recognition, andlose monitoring for signs and symp-oms of deterioration, such as an in-rease in abdominal tenderness and dis-ension, elevation of leukocyte countsver 20,000, or a rising creatinine level.23

n the case of progression to severe dis-ase with ileus or toxic megacolon, ade-uate delivery of vancomycin (ie, via na-ogastric or rectal tubing) to diseasedreas of the colon must be assured. Ad-itionally, in cases with progression toevere disease, it is essential to involveonsultants in a timely fashion, such asnfectious disease specialists, gastroen-erologists, and, particularly, generalurgeons. A subtotal colectomy can beifesaving in severe cases24: 3 of our pa-ients improved after resection of theiseased colon.A number of limitations, both in the

ase series and the survey, should be ac-nowledged. First, our case series is aonvenience sample, subject to both re-orting and selection biases, with the

ikelihood that there is bias toward theost severe presentations of disease. The

bsence of stool isolates of C difficilerom most cases and the nonstandard-zation of molecular typing through

NA extracts constitute another majorimitation. In addition, the 53% of polledhysicians who responded to our surveyay not be representative of all IDCs inorth America. Although recall biasay have inflated the rather low propor-

ion of respondents who reported know-ng of cases, it is unknown what propor-ion of all CDAD cases in peripartumomen are referred to IDCs in the first

lace. If this proportion is in fact low, it C

35.e6 American Journal of Obstetrics & Gynecolo

ould be a cause of large scale underre-orting. Repeating the survey and target-

ng obstetric and gynecology providershould be considered. f

CKNOWLEDGMENTShe authors wish to thank Shiraz Sunderji, MD,enise Jamieson, MD, Maya Gupta, MD,imisha Mishra, MD, Lalitha Koduri, MD, Paulyirjesy, MD, Jack Fitsimmons, MD, Davidtein, MD, Adrian Lata, MD.

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