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INFECTIOUS DISEASE

New data shed light on preventing cytomegalovirus infection and wound complications, and reveal a disturbing picture of Clostridium-related diarrhea in pregnant women.

June 2009 · Vol. 21, No. 06

IN THIS ARTICLE

Dr. Duff reports no financial relationships relevant to this article.

Four important developments have marked the past year in infectious disease:

  • A promising vaccine against cytomegalovirus (CMV) was tested in women of reproductive age
  • Extended-spectrum antibiotic prophylaxis proved to be effective in reducing the incidence of wound infection following cesarean delivery
  • Investigators developed a simple but effective method to prevent wound complications following repair of a third- or fourth-degree perineal laceration
  • The incidence of severe Clostridium difficile-associated diarrhea crept upward, emerging as a threat to pregnant women.

CMV vaccine makes an auspicious debut—but isn’t ready for practice

Pass RF, Zhang C, Evans A, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med. 2009; 360:1191–1199 [Classification of evidence – Level I].

This Phase-2, randomized, double-blind, placebo-controlled trial of a new cytomegalovirus (CMV) vaccine in women found an overall efficacy rate of 50% (95% confidence interval, 7% to 73%), with no unusually serious reactions among women who were vaccinated. This efficacy rate is disappointing, but it isn’t entirely surprising; even the immune response resulting from natural infection is not fully protective against reactivated infection or recurrent infection with a different strain of virus. Nor is natural immunity completely effective in preventing severe fetal injury in recurrent infection. 1

Virus poses greatest risk to pregnant women and their fetuses

CMV is the most common perinatally transmitted infection, affecting 0.6% to 0.7% of infants ( FIGURE 1 ). The greatest risk of fetal injury occurs when the mother develops primary infection during pregnancy, which raises her infant’s risk of infection to 40% to 50%. Of infants delivered to mothers with primary infection, approximately 10% to 15% will be acutely symptomatic at birth.

Clinical manifestations of severe congenital CMV infection include growth restriction, microcephaly, ventriculomegaly, intracranial calcification, chorioretinitis, hearing impairment, hepatitis, and thrombocytopenia.

Because the morbidity and mortality associated with these conditions are alarmingly high, development of a safe, effective vaccine against CMV would be most welcome. 2,3

Recurrent or reactivated maternal CMV infection poses a much lower risk to the fetus. Infected infants are rarely symptomatic at birth. Clinical manifestations of infection typically occur later in childhood and include hearing and visual deficits, dental anomalies, and learning or behavioral disorders. 2,3


FIGURE 1 Cytomegalovirus

Cytomegalovirus is a member of the herpesvirus family. It is shed intermittently in bodily fluids, without detectable signs and symptoms.

Details of the trial

Women were eligible for the study if they were seronegative for CMV antibody, in good health, 14 to 40 years old, and not pregnant or lactating. Participants received three doses of vaccine or placebo at 0, 1, and 6 months. (The vaccine was composed of CMV envelope glycoprotein B with MF59 adjuvant.) The women were then tested for CMV infection every 3 months for as long as 42 months, using an assay for IgG antibodies directed against viral proteins other than glycoprotein B. Infection was confirmed by viral culture or immuno blotting. The primary endpoint was time until detection of CMV infection.

The vaccine was given to 234 patients, and 230 received placebo. Eighteen infections occurred in the vaccine group, compared with 31 in the placebo group. Vaccinated patients were more likely to remain uninfected during follow-up (p=.02).

One of 81 infants (1%) born to mothers in the vaccinated group had congenital CMV infection, compared with three of 97 (3%) infants born to mothers in the placebo group (p=.41). One infant in the placebo group had severe infection that was evident at birth. The other three infants were asymptomatic at birth and free of sequelae 3 to 5 years later.

The most promising preventive remains experimental

No drug is uniformly effective in treating maternal CMV infection and preventing congenital infection. The most promising intervention for prevention of congenital CMV infection is administration of hyperimmune anti-CMV antibody to the mother. A recent report by Nigro and colleagues 4 found this agent to be of great value for both treating and preventing congenital CMV. However, because of limitations in the design of this study, administration of hyperimmune globulin still must be regarded as experimental. 3

Key questions remain unanswered

The goal of a large-scale vaccination program is to ensure that women enter reproductive age with preexisting immunity to infection. In that light, the study by Pass and colleagues is only partially encouraging. Despite vaccination, 18 infections occurred, and the follow-up period was relatively short. We do not yet know whether the protective effect of the vaccine will be of extended duration. Moreover, one vaccinated mother delivered an infant who had congenital CMV infection.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

Until additional trials of the CMV vaccine are reported, we must focus on helping patients prevent acquisition of infection during pregnancy. Preventive measures include:

  • safe sex practices
  • use of CMV-negative blood for transfusion to pregnant women and their fetuses
  • strict hand-washing procedures for mothers when changing diapers and caring for young children.

Extended-spectrum antibiotics reduce the rate of postcesarean wound infection

Tita ATN, Owen J, Stamm AM, Grimes A, Hauth JC, Andrews WW. Impact of extended-spectrum antibiotic prophylaxis on incidence of postcesarean surgical wound infection. Am J Obstet Gynecol. 2008;199:303e.1–303e.3 [Classification of evidence – Level II].

This prospective study describes surveillance for postcesarean wound infection during three different periods at the University of Alabama:

  • 1992–1996, during which patients undergoing cesarean delivery routinely received prophylaxis with a first- or second-generation cephalosporin. Overall incidence of wound infection: 3.1%
  • 1997–1999, during which patients were randomized to standard prophylaxis with cefazolin or to cefazolin plus either intravenous (IV) doxycycline or oral azithromycin. Overall incidence of wound infection: 2.4%
  • 2001–2006, during which patients routinely received IV cefazolin plus IV azithromycin. Overall incidence of wound infection: 1.3%.

In each time period, the prophylactic antibiotics were administered after the infant’s umbilical cord was clamped. The p value for test of trend was highly significant (p<.002). The same significant trend was noted when superficial and deep wound infections were examined separately.

This evidence is a “practice changer”

For almost 20 years, the standard of practice has been to routinely administer prophylactic antibiotics to all women having cesarean delivery. Essentially, every published study has demonstrated a highly significant reduction in the frequency of postcesarean endometritis when patients received prophylaxis. Multiple studies also confirmed that a more limited-spectrum cephalosporin was as effective as an extended-spectrum agent in reducing the frequency of endometritis. 5

Many of these earlier reports were unable to demonstrate a consistently beneficial effect of prophylaxis on the incidence of postoperative wound infection. That is why the present study is of such interest and importance. Tita and colleagues previously demonstrated an improved effect of extended-spectrum prophylaxis on the incidence of postcesarean endometritis. 6 Now they have confirmed that this method of prophylaxis is also effective in lowering the rate of surgical wound infection.

Wound infections are more troublesome than endometritis

Wound infections—either incisional abscess or cellulitis—are even more likely than post-cesarean endometritis to prolong a patient’s postoperative stay and create the potential for severe morbidity, such as fascial dehiscence and necrotizing fasciitis. With the increasing prevalence of obesity in the US population, wound infections are likely to become even more frequent.

These infections typically are caused by aerobic streptococci and staphylococci from the skin, combined with coliform organisms and anaerobes from the pelvic flora. Incisional abscesses require surgical drainage; cellulitis usually will respond to a change in antibiotic therapy that specifically targets streptococci and staphylococci, along with the coliforms and anaerobes.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

I strongly recommend routine prophylaxis with IV cefazolin (1 g) plus azithromycin (500 mg) in all women having cesarean delivery. Moreover, in view of several recent investigations that evaluated the timing of antibiotic administration (immediately preoperative versus after the umbilical cord is clamped), I recommend that extended-spectrum prophylaxis be given before the start of surgery. 7

Prophylactic antibiotics reduce the complication rate by 2/3 after repair of major perineal laceration

Duggal N, Mercado C, Daniels K, Bujor A, Caughey AB, El-Sayed YY. Antibiotic prophylaxis for prevention of postpartum perineal wound complications: a randomized control trial. Obstet Gynecol. 2008;111:1268–1273 [Classification of evidence – Level I].

Take note of this prospective, randomized, placebo-controlled trial of prophylactic antibiotics in women who sustained a third-or fourth-degree perineal laceration during vaginal delivery: It is the first, and only, well-designed trial of antibiotic prophylaxis for prevention of complications after repair of a major perineal laceration. Among patients in the study, 8% who received antibiotics developed a wound complication, compared with 24% of patients who received placebo, a statistically and clinically significant difference.

Details of the study

Eighty-three women received placebo, and 64 received a single IV dose of either cefotetan (1 g) or cefoxitin (1 g) before their perineal laceration was repaired. Patients who were allergic to penicillin received clindamycin (900 mg). The primary endpoints of the study were gross disruption of the wound or purulent drainage from the wound site 2 weeks after delivery.

Forty patients (27%) did not return for their post-partum appointment. Of the remaining patients, four of 49 (8%) who received antibiotics developed a wound complication, compared with 14 of 58 (24%) of those who received placebo (p=.037).

Sequelae of major perineal laceration can be severe

Major perineal laceration occurs in approximately 2% to 20% of vaginal deliveries in the United States. The principal risk factors for third- and fourth-degree lacerations are nulliparity, midline episiotomy, and operative vaginal delivery, especially forceps extraction. Both types of laceration may lead to serious morbidity, such as prolonged pain, fecal incontinence, and perineal infection, including necrotizing fasciitis. These infections typically are polymicrobial, mixed aerobic–anaerobic. Moreover, fourth-degree lacerations may result in rectovaginal fistula if they are not repaired properly. This complication causes considerable debility and major social inconvenience for the patient.

Although the sample size was relatively small, this study clearly demonstrated that a single dose of extended-spectrum cephalosporin (cefotetan or cefoxitin) was highly effective in reducing the rate of perineal infection and perineal wound disruption. Whether a more limited-spectrum agent such as cefazolin would be as effective is not certain.

WHAT THIS EVIDENCE MEANS FOR PRACTICE

I strongly recommend routine antibiotic prophylaxis for any patient who sustains a third- or fourth-degree perineal laceration.

If the patient has a mild allergy to penicillin (morbilliform rash), I would administer cefotetan because it is less expensive than cefoxitin. If the patient has a severe reaction to penicillin (urticaria, anaphylaxis), I would administer both clindamycin and gentamicin in order to ensure adequate coverage of the multiple organisms likely to cause soft-tissue infection of the genital tract.

Clindamycin alone covers only aerobic gram-positive cocci and offers no protection against the coliform organisms that are so prevalent in perineal wound infection. 8

Diarrhea linked to Clostridium difficile emerges as a potent threat to pregnant women

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 [Classification of evidence – Level III].

Continued...
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