Cape, Alison MD; Tuomala, Ruth E. MD; Taylor, Chirisse MPH; Puopolo, Karen M. MD, PhD
Infection is the single most common medical problem encountered in pregnancy.1 Overall febrile morbidity is common, affecting 5–10% of all pregnant women.2 Although the absolute rate of mortality from pregnancy-associated infection is low (approximately 0.02 per 1,000 live births in the United States), 10–11% of all maternal mortalities in the United States are attributed to infection.3 In addition to the short-term financial and social costs of maternal infection and the potential long-term effects on maternal health, peripartum infection is associated with abnormal neurologic development in children born in the setting of such infection.4
Despite the potentially serious consequences of severe maternal infection, few studies have examined the causative organisms and clinical correlates of sepsis among obstetric patients.5–7 Only one study5 exclusively examined the peripartum time period, whereas others include all obstetric and gynecologic patients6 or all obstetric admissions (including antepartum).7 Furthermore, there are no data available for the spectrum of invasive maternal disease since the widespread implementation of intrapartum antibiotic prophylaxis to prevent neonatal sepsis in neonates born to women with group B streptococcus colonization. The transition from selective screening to risk factor-based screening to universal antepartum group B streptococcus screening has increased the rate of intrapartum antibiotic use.8 The Centers for Disease Control and Prevention (CDC) multistate surveillance from 2003 to 2004 reported that intrapartum antibiotics were used among approximately 32% of laboring women.9 Intrapartum antibiotics were used in approximately 40% of vaginal deliveries in our maternity center in 2007.10 The purpose of our study was to describe the overall incidence, clinical correlates, microbiology, and antibiotic sensitivity of peripartum bacteremia in a maternity center that utilizes universal screening–based group B streptococcus intrapartum antibiotic prophylaxis.
MATERIALS AND METHODS
This was a retrospective cohort study conducted at Brigham and Women's Hospital in Boston, Massachusetts, among women delivering from January 2000 to December 2008. The study was approved by our local Institutional Review Board and the Partners Healthcare Human Research Committee, and was deemed exempt from informed consent.
We defined the peripartum period as 7 days antepartum until 30 days postpartum. We reviewed the hospital microbiology database to identify all blood cultures obtained from obstetric inpatients and outpatients during this period. The date of delivery was compared with date of culture to identify peripartum cultures. Only women delivering after 24 weeks of gestation were included in the study. Bacteremia cases associated with the presence of central lines and bacteremia cases caused by common skin contaminants (including, for example, coagulase-negative staphylococci, micrococcus, and diphtheroids species) were eliminated from consideration.
During the study period, all obstetric providers at Brigham and Women's Hospital adhered to a universal screening-based policy for the administration of group B streptococcus intrapartum antibiotic prophylaxis or to a risk-based approach to group B streptococcus intrapartum antibiotic prophylaxis if screening results were unknown at presentation for delivery, per CDC guidelines.11,12 Penicillin G was the recommended primary antibiotic to be administered for group B streptococcus intrapartum antibiotic prophylaxis unless maternal penicillin allergy was documented. Women presenting with preterm premature rupture of the membranes were treated with intravenous penicillin for group B streptococcus prophylaxis until delivery if preterm premature rupture of the membranes was associated with labor, or until premature labor was ruled out. Women with preterm premature rupture of the membranes who were expectantly managed were subsequently treated with erythromycin or a combination of amoxicillin and erythromycin for a maximum of 7 days of antibiotic treatment. Perioperative antibiotic prophylaxis with cefazolin (or clindamycin and gentamicin in the case of beta-lactam allergy) was administered within 60 minutes before incision for all cesarean deliveries. For febrile peripartum women (oral temperature 100.4°F or higher) with clinical signs and symptoms suggestive of infection, standard obstetric practice was to obtain aerobic and anaerobic blood cultures utilizing two separate venous blood samples. Antibiotics were administered to febrile peripartum women after blood cultures were obtained, most commonly ampicillin, gentamicin, and clindamycin unless maternal penicillin allergy was documented. Blood culture isolate identification and antibiotic susceptibility testing were performed by the hospital laboratory.
Medical records were reviewed to obtain maternal and neonatal demographic data, diagnoses assigned by the obstetric provider, mode of delivery, gestational age at delivery, and adverse outcomes associated with maternal bacteremia. Risk ratios were calculated using Microsoft Excel by dividing the rate of development of bacteremia attributable to endometritis after a cesarean delivery compared with the rate of development of bacteremia attributable to endometritis after a vaginal delivery. This also was calculated for term (37 or more weeks of gestation) compared with preterm delivery (24 to 36 weeks plus 6 days of gestation) using data from 2000 to 2007 only. For comparison of clinical characteristics of infected and noninfected women, characteristics were compared using Fisher exact test or t test as appropriate; P<.05 was considered significant.
During the study period, 78,781 women delivered 81,376 live neonates; cesarean deliveries accounted for 23.9% of all deliveries. Blood cultures were obtained from 1,295 peripartum women (1.6% of all parturients). All blood cultures were obtained because of maternal fever (temperature 100.4°F [38°C] or higher). A comparison of the clinical characteristics of women with true bacteremia and those with negative blood cultures, or cultures deemed contaminants, is shown in Table 1. On univariate analysis, bacteremia was associated with white race, cesarean delivery, preterm delivery, and nonsingleton delivery, and most bacteremic cultures were found during the postpartum period.
Thirty-four of the 1,295 cultures (2.6%) had a contaminant as their only positive culture. True positive bacteremia occurred in 172 women (incidence 2.2 cases per 1,000 deliveries; 13.3% of total women sampled). Of these women, 31 were known to be group B streptococcus screen–positive, 116 were known to be group B streptococcus screen–negative, and 25 had unknown group B streptococcus status. In 25 of 27 women, the unknown group B streptococcus status was attributable to preterm delivery before group B streptococcus culture was obtained, and all were treated with group B streptococcus intrapartum antibiotic prophylaxis. In one case, unknown status was attributable to inadequate prenatal care and intrapartum antibiotic prophylaxis was started once rupture of membranes reached 18 hours. The final case was attributable to transfer of care without records and no intrapartum antibiotic prophylaxis was administered because of the absence of risk factors for group B streptococcus disease.
Among the 172 women with true bacteremia, there were 21 cases of polymicrobial infections, each with 2 or 3 isolated organisms; thus, the study includes a total of 194 bacterial isolates and 1 yeast isolate (Candida albicans). Two women had three isolates: one woman with preeclampsia had development of disseminated intravascular coagulation and renal failure, and a combination of enterococcus, Enterobacter species, and Klebsiella species grew; the second woman had urosepsis diagnosed and had a combination of Escherichia coli, enterococcus, and C albicans. Overall, the most frequent individual bacterial isolates were E coli, enterococci, and anaerobic species (Table 2); group B streptococcus was isolated in only eight cases (4.1%). Selected clinically relevant antibiotic sensitivities of the bacterial isolates were examined. All group B streptococcus blood isolates were sensitive to penicillin; three of eight were resistant to clindamycin and four of eight were resistant to erythromycin. Among nine Staphylococcus aureus isolates, three of nine were methicillin-resistant. Of the 46 enterococcal isolates, 43 of 46 were sensitive to ampicillin. Two women were infected with vancomycin-resistant Enterococcus faecium. Half of the E coli isolates (35 of 70 isolates, 50%) were resistant to ampicillin, but only two isolates were classified as extended-spectrum β-lactamase organisms. Antibiotic sensitivity testing is not routinely performed for anaerobic isolates at our institution. Overall, assuming that anaerobic species were sensitive to clindamycin, 59 of 195 (30.3%) identified organisms would require a change in antibiotic therapy from the empiric combination of ampicillin, gentamicin, and clindamycin.
The characteristics of women with group B streptococcus bacteremia are shown in Table 3. In six of eight cases, maternal group B streptococcus status was unknown or reported as negative. In only one case (patient 1) was appropriate screening-based group B streptococcus intrapartum antibiotic prophylaxis administered; in another case, penicillin G was administered on a risk factor–based approach (patient 5). In two cases, women received clindamycin but the group B streptococcus blood isolates were resistant to clindamycin. The CDC guidelines for neonatal group B streptococcus prevention recommend use of clindamycin for penicillin-allergic women only when isolate resistance profile is known because of the high level of resistance to clindamycin among United States group B streptococcus isolates.12 In these cases the patients did not have a documented penicillin allergy, and there was no group B streptococcus antibiotic sensitivity profile known in patient 6. The reasons for these antibiotic choices could not be determined.
Clinical diagnoses associated with intrapartum and postpartum onset of infection included chorioamnionitis (21%), endometritis (56%), and urosepsis (8%), which together accounted for most cases; wound infection and bacteremia without an identified source together accounted for the remaining cases (Fig. 1). Among women for whom endometritis was the primary diagnosis (n=97), 77.3% delivered by cesarean (relative risk [RR] 10.85, 95% confidence interval [CI] 6.75–17.45 compared with vaginal delivery) and 39.2% delivered at less than 37 weeks of gestation (RR 3.21, 95% CI 2.42–4.25 compared with delivery at 37 weeks or greater [using 2000–2007 data only]).
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Severe maternal complications of bacteremia were noted in 10.5% of bacteremic women. One death occurred in association with postpartum urosepsis. Six women had development of systemic inflammatory response syndrome as a consequence of endometritis (two women), urosepsis (one woman), and chorioamnionitis (three women), and five of these women were admitted to the intensive care unit. Six women had development of disseminated intravascular coagulation, two of whom required intensive care unit admission. Five women had development of ileus, one of which was complicated by intestinal perforation requiring emergency ileoostomy.
A total of 200 neonates were born to bacteremic women, and 1,226 neonates were born to nonbacteremic women who had cultures tested. Seven neonates born to bacteremic mothers died before discharge home; six of seven were premature, with gestational ages at birth ranging from 25 to 29 weeks, and one was born at term. One fetal death occurred in a woman with group B streptococcus bacteremia. Among the nonbacteremic women who had cultures tested, 20 neonatal deaths and 20 fetal deaths occurred. The combined incidence of death or fetal death was not significantly different between bacteremic and nonbacteremic women (4% compared with 3.3%; P=.831). In six cases, neonates had blood cultures obtained soon after birth that grew the same bacteria that was isolated from the maternal blood cultures. In three cases, both mother and neonate had E coli. In one case, both mother and neonate had E coli and Klebsiellapneumoniae infection. In one case, mother and neonate had Bacteroidesfragilis infection. In one case, both mother and neonate had Listeria monocytogenes.
We found a considerable incidence of bacteremia among febrile peripartum women evaluated for infection in the era of group B streptococcus prophylaxis. Among those women who had cultures tested, approximately 13% were bacteremic with pathogenic species and 30% of these organisms required changes in antibiotic therapy from the empiric combination of ampicillin, gentamicin, and clindamycin. In the era of group B streptococcus prophylaxis, approximately 60% of bacteremia was caused by E coli or enterococci.
The goal of our study was to describe the microbial epidemiology of peripartum bacteremia in a center with routine screening-based group B streptococcus intrapartum antibiotic prophylaxis and a relatively high overall use of intrapartum antibiotic exposure.10 Within this description, there are several findings of practical importance. First, our study does not support an important effect of routine screening-based group B streptococcus intrapartum antibiotic prophylaxis on the overall incidence of maternal peripartum bacteremia in comparison with published studies performed before the widespread use of group B streptococcus intrapartum antibiotic prophylaxis. We observed an incidence of bacteremia of 2.2 cases per 1,000 deliveries among febrile peripartum women within range of studies that report one to seven bacteremia cases per 1,000 obstetric admissions or deliveries before group B streptococcus intrapartum antibiotic prophylaxis.5–7 Our findings of the incidence of bacteremia are in contrast to data suggesting that increased use of group B streptococcus intrapartum antibiotic prophylaxis may decrease the incidence of maternal peripartum disease. Dumas et al13 reported that the rate of endometritis was 0.25% in women not receiving group B streptococcus intrapartum antibiotic prophylaxis compared with 0.11% in treated women, although group B streptococcus intrapartum antibiotic prophylaxis did not affect the incidence of urinary tract infection. Similarly, decreased incidences of endometritis (RR 0.68) and chorioamnionitis (RR 0.71) were observed in a large medical center after a transition from selective group B streptococcus screening to a universal group B streptococcus culture–based program for intrapartum antibiotic prophylaxis,8 although that study did not account for the concurrent introduction of routine antibiotic prophylaxis at the time of cesarean delivery.
Another important finding of our study is the relatively low incidence of maternal group B streptococcus–specific bacteremia associated with screening-based group B streptococcus intrapartum antibiotic prophylaxis (0.1 cases per 1,000 live births, or 4% of documented bacteremia). These findings are consistent with CDC multistate active surveillance data from 1999 to 2005 that reported 0.12 cases of invasive group B streptococcus disease per 1,000 live births among pregnant women, of which bacteremia accounted for approximately one third of the cases.14 In a study of peripartum bacteremia in Finland, during a period in which the study site did not use group B streptococcus intrapartum antibiotic prophylaxis, group B streptococcus was the cause of 19% of all maternal bacteremia cases and 50% of bacteremia cases that occurred after a vaginal delivery. Review of obstetric blood cultures at our institution from 1993 to 1996, before the implementation of a universal screening-based policy for group B streptococcus prophylaxis, reveals that approximately 12% of obstetric bacteremia cases were attributable to group B streptococcus (data not shown). Other studies of bacteremia among pregnant women before group B streptococcus intrapartum antibiotic prophylaxis that were not limited to the peripartum period found that group B streptococcus caused 10–15% of maternal bacteremia cases.6,7 As has been the experience with neonatal group B streptococcus bacteremia in the era of group B streptococcus prophylaxis,15,16 our study demonstrates that maternal group B streptococcus bacteremia has not been eliminated. Maternal disease was associated with group B streptococcus–negative status and unknown maternal group B streptococcus status, and occurred despite receipt of both appropriate and inappropriate antibiotics for group B streptococcus intrapartum antibiotic prophylaxis.
Our study has several limitations. The retrospective observational design does not allow us to quantitate the effect of peripartum antibiotic exposure on the incidence of bacteremia in comparison with an earlier period of time. The study was not designed to develop a predictive model for peripartum bacteremia; for example, we cannot determine whether cesarean delivery or preterm delivery is a stronger predictor of peripartum bacteremia, and nonsingleton delivery is associated with both cesarean and preterm delivery. Although our local obstetric policy mandates that blood cultures should be obtained in febrile peripartum women, we did not examine compliance with this policy; thus, our study sample may not be fully representative of all febrile peripartum women. However, our study does provide information that may guide evaluation for and empiric treatment of maternal bacteremia in the era of group B streptococcus prophylaxis. In our population, obligate anaerobes accounted for nearly 15% of cases, highlighting the importance of using both aerobic and anaerobic blood culture bottles when evaluating febrile obstetric patients. Highly antibiotic-resistant disease, such as methicillin-resistant S aureus, vancomycin-resistant E faecium, extended-spectrum β-lactamase Gram-negative infection, and Candida albicans, together accounted for approximately only 4% of all isolates, meaning that the empiric use of very broad-spectrum antibiotics to account for such organisms currently is not justified. The majority of aerobic Gram-negative infections (E coli, Klebsiella, Morganella, and Enterobacter species) were resistant to ampicillin, however, and this suggests that the inclusion of ampicillin in empiric antibiotic treatment of peripartum bacteremic may be questioned. The relatively high overall incidence of bacteremia, the diversity of bacterial isolates, the presence of antibiotic-resistant disease in a majority of cases, and the severity of complications among bacteremic women all support an important role for blood culture testing in the febrile peripartum population to ensure optimal antibiotic therapy.
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