AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 6 November 7997
CLOSTRIDIAL INFECTION AS A CAUSE OF FULMINANT CONGENITAL SEPSIS NEONATORUM
Clostridia spp are anaerobic gram-positive spore forming baccilli that are common inhabitants of the gastrointestinal tract and, less commonly, of the female genital tract.1-2 Despite this distribution, clostridial infection in the fetus and newborn infant is relatively rare.3-4 Clostridial septicemia has been described in the newborn infant after invasive procedures such as surgery5"7 or in association with devitalized tissue, such as the umbilical stump in the case of omphalitis.8"10 We recently cared for two infants who presented at birth with fulminant congenital sepsis who died despite aggressive medical therapy. The clinical presentation and subsequent postmortem findings implicated Clostridium as the primary pathogen. This report represents a review of the clinical manifestations of this infection in these infants as well as a review of the pertinent medical literature. CASE REPORTS Case 1
A 1700 gm female infant was born to a 31-yearold primigravida at 34 weeks' gestation. The mother was admitted 3 weeks prior to delivery for management of preeclampsia. Oxytocin induction of labor was started 24 hours prior to delivery, because of worsening preeclampsia. Clear amniotic fluid was noted after artificial rupture of the membranes 16 hours before delivery. Maternal cervical cultures were negative for group B Streptococcus. A fetal scalp electrode and intrauterine pressure catheter were placed. Short- and long-term fetal heart rate variability was noted to be poor with a baseline rate of 140 to 150 beats/minute (bpm). Shortly before delivery, fetal heart rate decelerations were noted, followed by a prolonged fetal bradycardia with a return to the baseline rate before delivery. The infant was limp and unresponsive and was intubated immediately; cardiopulmonary resuscitation was initiated. Apgar scores were 1 and 1 at 1 and 5 minutes. Umbili-
cal cord blood gases were as follows: venous pH 6.81 and arterial pH 6.57 with a bicarbonate of 6.9 mmol/ liter. The infant was appropriately grown with no external anomalies. She was pale, mottled, and cyanotic with thready pulses and poor capillary refill. Bleeding was noted from heel sticks, intravenous punctures, the oropharynx, and the endotracheal tube. She died at 5V2 hours of life. Unfortunately, no cultures were obtained prior to the infant's death. The mother remained on magnesium sulfate for 24 hours. She initially had a tender uterus with a white blood cell count of 54.4 x 103/mm3 with 72% band and 24% segmented forms and she was started on intravenous ampicillin. She remained afebrile and the uterine tenderness cleared within 3 hours of delivery. Urine culture grew group D Streptococcus. At postmortem examination, tissue Gram's stains of the placenta showed numerous gram-positive and gram-variable rods, some with subterminal spores, along the chorionic plate, along the fetal membranes, and within the umbilical cord blood vessels (Fig. 1). The lungs also showed evidence of amniotic fluid aspiration and pneumonia. Gram-positive and gram-variable rods were noted in the airways and lung parenchyma as well (Fig. 2). Postmortem blood, placenta, and lung cultures were negative. Case 2
A 1120 gm male infant was born to a 26-year-old multigravida at 29 weeks' gestation. Premature rupture of membranes was noted 7 days before delivery. Spontaneous onset of labor was noted 24 hours before delivery. Fetal heart rate monitoring revealed tachycardia with decreased beat-to-beat variability. Maternal white blood cell count was 16.3 x 103/mm3 with 34% bands and 56% neutrophils. Vaginal breech delivery occurred shortly thereafter. The amniotic fluid was noted to be foul smelling and a 20% placental abruption was noted. Respiratory distress requiring intubation was noted immediately after birth.
Department of Pediatrics, Division of Newborn Medicine, The Pennsylvania State University, The Milton S. Hershey Medical Center, Hershey, Pennsylvania *Division of Neonatology, Cape Fear Valley Medical Center, P.O. Box 2000, Fayetteville, North Carolina Reprint requests: Dr. Gallaher, Division of Neonatology, Cape Fear Valley Medical Center, P.O. Box 2000, Fayetteville, NC 28302 370
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
Keith J. Gallaher, M.D.* and Keith H. Marks, M.D., Ph.D.
CLOSTRIDIAL INFECTION/Gallaher, Marks
Streptococcus viridans. Microscopic examination of the placenta showed severe (stage III) acute and chronic chorioamnionitis with moderate villous edema. No placental Gram's stain or postmortem examination were performed. The mother was treated with ampicillin and was discharged home on postpartum day 1.
Figure 1. The left panel is a representative tissue Gram's stain of the membranes covering the umbilical cord. Sheets of gram-positive rods (arrowheads) are noted along the surface facing the amniotic fluid (AF) cavity. Numerous gram-positive rods are also noted within the lumen (L) of the umbilical artery (arrowheads, right panel), (x 750.)
•, •
$i Figure 2. The left panel is a representative hematoxylin and eosin stained section through a bronchus demonstrating large amounts of intraluminal (L) debris and squamous epithelial cells (arrows). Tissue Gram's stain of a similar section (right panel) reveals numerous intraluminal grampositive rods. These findings confirm the clinical diagnosis of aspiration pneumonia, (x 750.)
Apgar scores were 2 and 7 at 1 and 5 minutes, respectively. Umbilical cord gases were as follows: venous pH 7.29 and arterial pH 7.03 with a bicarbonate of 15.3 mmol/liter. He was an appropriately grown infant without anomalies. His vital signs became progressively more unstable throughout the day with hypotension, cyanosis, and the eventual development of intractable metabolic acidosis. Echocardiogram showed pulmonary hypertension without evidence of structural heart disease. Chest radiographs showed homogeneous alveolar densities. Management included antibiotics (ampicillin and gentamycin), intravenous immunoglobulin, fresh frozen plasma, dopamine, and high-frequency jet ventilation. Despite this management, he died at 15 hours of age. Spun hematocrits revealed evidence of intravascular hemolysis with the serum being red. Blood culture eventually returned as positive for Clostridium perfringens and
These two infants with congenital sepsis presented with clinical findings strongly suggestive of overwhelming Clostridial infection. Although no culture results were obtained to substantiate the diagnosis in case 1, the histologic findings of grampositive and gram-variable bacilli with subterminal spores strongly implicate Clostridia as being the etiology. The clinical findings of obtundation, shock, and intravascular hemolysis that were seen in both cases have been well described with Clostridial infection, primarily in the clinical setting of gas gangrene. This presentation is generally believed to be due to the elaboration of exotoxin, especially a phospholipase, alpha toxin. This most often accompanies a localized infection of devitalized tissue and can result in cardiovascular collapse and death before a bacteremia is evident.9 The presentation of Clostridial infection in these infants was rather unusual in that there was no obvious devitalized tissue to support the origin of an anaerobic infection. Both infants, however, were premature and were born to mothers with the clinical diagnosis of chorioamnionitis, a diagnosis later confirmed by histologic examination of the placenta. Anaerobic bacteria are commonly associated with chorioamnionitis3 and are generally of low virulence. Infants born to mothers with chorioamnionitis due to anaerobic infection generally do well. Since both of the mothers had been hospitalized prior to their deliveries, it is possible that the Clostridial organisms were introduced iatrogenically. More likely, the infection and rapid death of these infants were unfortunate complications of chorioamnionitis in infants who were relatively immune deficient because of their prematurity. On review of the literature, only four other cases of congenital Clostridial sepsis could be identified (Table I). 41 !-13 This may be an underestimate of the prevalence of this infection, since some infants (especially those born prematurely) likely die before accurate diagnosis can be made. Interestingly, two of the reported cases describe systemic infections involving both mother and infant. Both of these infants were delivered by emergency cesarean section and maternal morbidity was related, at least in part, to involvement of the surgical wound. The relatively benign postpartum course of the two mothers presented herein is likely related to the avoidance of cesarean delivery. Including the historical cases where clinical information is provided, there are several common 371
Downloaded by: National University of Singapore. Copyrighted material.
DISCUSSION
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 6
Congenital Sepsis Due to Clostridia spp.
Isolated
Chowetal (1974) Chaney (1980) Akonkhai et al (1981) Orzel etal (1983) Gallaher and Marks (1991)
Blood Maternal blood, infant blood Placenta, blood Placenta, maternal blood, gastric aspirate Blood Placenta, lungs
perinatal factors; however, none of these are unique for Clostridial infection. The majority of the cases (four of five) presented with chorioamnionitis. Evidence of fetal distress (four offive)and premature or prolonged rupture of the membranes (three of five) were also noted. Premature birth has only been described in the two infants in this report. The clinical manifestations are similar to those described for typical cases of gas gangrene.9 Evidence of intravascular hemolysis, respiratory distress, and disseminated intravascular coagulopathy were seen in the majority of the cases reported. Clostridium spp are very susceptible to treatment with penicillin. Since in the cases reviewed devitalized tissue was not a source of infection, the value of adjunctive treatments such as hyperbaric oxygen seems small. If as suggested by Orzel et al11 the placenta, membranes, or amniotic fluid are the sources of infection, then the source would be removed by delivery. The overall mortality in this series of congenital Clostridial sepsis is two of six (33%), with both deaths occurring in the prematurely born infants described herein. Interestingly, the infant reported by Orzel et al survived after undergoing an exchange transfusion. Since much of the systemic illness is toxin mediated, perhaps the combination of antibiotics and exchange transfusion resulted in a more rapid removal of systemic exotoxin. The first step in adequate treatment of an illness is its rapid clinical recognition. Physicians caring for infants in the immediate postnatal period need to be aware that fulminant sepsis with intravascular hemolysis may be due to Clostridial infection. Although two thirds of the infants reported herein survived, it is possible that the most severely ill infants die undiagnosed and unreported. This infection appears to be especially devastating in the prematurely born infant. In this situation, it is interesting to speculate whether supportive therapy such as exchange trans-
372
Outcome
Lived Lived Lived Lived Died Died
Type
C. C. C. C. C.
perfringens perfringens perfringens perfringens perfringens —
fusion aimed at removing the exotoxin may improve outcome over systemic antibiotics alone. REFERENCES 1. Kelsall GRH, Barter RA, Manessis C: Prospective bacteriological studies in inflammation of the placenta, cord, and membranes. J Obstet Gynaecol Br Commonw 74: 401-411, 1967 2. Gorbach SL, Thadepalli M: Isolation of Clostridium in human infections. J Infect Dis 131:S81-S85, 1975 3. Pankuch GA, et al: Placental microbiology and histology and the pathogenesis of chorioamnionitis. Obstet Gynecol 64:802-806, 1984 4. Chow AW, Leake RD, Yamanchi T, Anthony BF, Guze LB: The significance of anaerobes in neonatal bacteremia: Analysis of 23 cases and review of the literature. Pediatrics 54:736-745, 1974 5. Long JG, Preblud SR, Keyserling HL: Clostridium perfringens meningitis in an infant; case report and literature review. Pediatr Infec Dis 6:752-754, 1987 6. Freedman S, Hollander M: Clostridium perfringens septicemia as a postoperative complication of the newborn infant. J Pediatr 71:576-578, 1967 7. Isenberg AN: Clostridium welchii infection: A clinical evaluation. Arch Surg 92:727-731, 1966 8. Bogdan JC, Rapkin RH: Clostridia infection in the newborn. Pediatrics 58:120-122, 1976 9. Stunden RJ, Brown RA, Rode H, Millar AJW, Cywes S: Umbilical gangrene in the newborn. J Pediatr Surg 23: 130-134, 1988 10. Walker SH, Macaraeg El: Neonatal sepsis due to Clostridium perfringens. Md State Med J 22:61-62, 1973 11. Orzel JA, Cohen DL, McDonald EC, Gandy G: Clostridium perfringens sepsis involving mother and neonate with survival of both. Pediatr Infect Dis 2:457-459, 1983 12. Chaney NE: Clostridium infection in mother and infant. Am J Dis Child 134:1175-1176, 1980 13. Ahonkhai, VI, Kim MH, Raziuddin K, et al: Perinatal Clostridium perfringens infection. Clin Pediatr (Phila) 20:532-533,1981
Keith J. Gallaher is the recipient of National Research Service Award HL07589.
Downloaded by: National University of Singapore. Copyrighted material.
Table 1.
November 1991
CLOSTRIDIAL INFECTION AS A CAUSE OF FULMINANT CONGENITAL SEPSIS NEONATORUM
Clostridia spp are anaerobic gram-positive spore forming baccilli that are common inhabitants of the gastrointestinal tract and, less commonly, of the female genital tract.1-2 Despite this distribution, clostridial infection in the fetus and newborn infant is relatively rare.3-4 Clostridial septicemia has been described in the newborn infant after invasive procedures such as surgery5"7 or in association with devitalized tissue, such as the umbilical stump in the case of omphalitis.8"10 We recently cared for two infants who presented at birth with fulminant congenital sepsis who died despite aggressive medical therapy. The clinical presentation and subsequent postmortem findings implicated Clostridium as the primary pathogen. This report represents a review of the clinical manifestations of this infection in these infants as well as a review of the pertinent medical literature. CASE REPORTS Case 1
A 1700 gm female infant was born to a 31-yearold primigravida at 34 weeks' gestation. The mother was admitted 3 weeks prior to delivery for management of preeclampsia. Oxytocin induction of labor was started 24 hours prior to delivery, because of worsening preeclampsia. Clear amniotic fluid was noted after artificial rupture of the membranes 16 hours before delivery. Maternal cervical cultures were negative for group B Streptococcus. A fetal scalp electrode and intrauterine pressure catheter were placed. Short- and long-term fetal heart rate variability was noted to be poor with a baseline rate of 140 to 150 beats/minute (bpm). Shortly before delivery, fetal heart rate decelerations were noted, followed by a prolonged fetal bradycardia with a return to the baseline rate before delivery. The infant was limp and unresponsive and was intubated immediately; cardiopulmonary resuscitation was initiated. Apgar scores were 1 and 1 at 1 and 5 minutes. Umbili-
cal cord blood gases were as follows: venous pH 6.81 and arterial pH 6.57 with a bicarbonate of 6.9 mmol/ liter. The infant was appropriately grown with no external anomalies. She was pale, mottled, and cyanotic with thready pulses and poor capillary refill. Bleeding was noted from heel sticks, intravenous punctures, the oropharynx, and the endotracheal tube. She died at 5V2 hours of life. Unfortunately, no cultures were obtained prior to the infant's death. The mother remained on magnesium sulfate for 24 hours. She initially had a tender uterus with a white blood cell count of 54.4 x 103/mm3 with 72% band and 24% segmented forms and she was started on intravenous ampicillin. She remained afebrile and the uterine tenderness cleared within 3 hours of delivery. Urine culture grew group D Streptococcus. At postmortem examination, tissue Gram's stains of the placenta showed numerous gram-positive and gram-variable rods, some with subterminal spores, along the chorionic plate, along the fetal membranes, and within the umbilical cord blood vessels (Fig. 1). The lungs also showed evidence of amniotic fluid aspiration and pneumonia. Gram-positive and gram-variable rods were noted in the airways and lung parenchyma as well (Fig. 2). Postmortem blood, placenta, and lung cultures were negative. Case 2
A 1120 gm male infant was born to a 26-year-old multigravida at 29 weeks' gestation. Premature rupture of membranes was noted 7 days before delivery. Spontaneous onset of labor was noted 24 hours before delivery. Fetal heart rate monitoring revealed tachycardia with decreased beat-to-beat variability. Maternal white blood cell count was 16.3 x 103/mm3 with 34% bands and 56% neutrophils. Vaginal breech delivery occurred shortly thereafter. The amniotic fluid was noted to be foul smelling and a 20% placental abruption was noted. Respiratory distress requiring intubation was noted immediately after birth.
Department of Pediatrics, Division of Newborn Medicine, The Pennsylvania State University, The Milton S. Hershey Medical Center, Hershey, Pennsylvania *Division of Neonatology, Cape Fear Valley Medical Center, P.O. Box 2000, Fayetteville, North Carolina Reprint requests: Dr. Gallaher, Division of Neonatology, Cape Fear Valley Medical Center, P.O. Box 2000, Fayetteville, NC 28302 370
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
Downloaded by: National University of Singapore. Copyrighted material.
Keith J. Gallaher, M.D.* and Keith H. Marks, M.D., Ph.D.
CLOSTRIDIAL INFECTION/Gallaher, Marks
Streptococcus viridans. Microscopic examination of the placenta showed severe (stage III) acute and chronic chorioamnionitis with moderate villous edema. No placental Gram's stain or postmortem examination were performed. The mother was treated with ampicillin and was discharged home on postpartum day 1.
Figure 1. The left panel is a representative tissue Gram's stain of the membranes covering the umbilical cord. Sheets of gram-positive rods (arrowheads) are noted along the surface facing the amniotic fluid (AF) cavity. Numerous gram-positive rods are also noted within the lumen (L) of the umbilical artery (arrowheads, right panel), (x 750.)
•, •
$i Figure 2. The left panel is a representative hematoxylin and eosin stained section through a bronchus demonstrating large amounts of intraluminal (L) debris and squamous epithelial cells (arrows). Tissue Gram's stain of a similar section (right panel) reveals numerous intraluminal grampositive rods. These findings confirm the clinical diagnosis of aspiration pneumonia, (x 750.)
Apgar scores were 2 and 7 at 1 and 5 minutes, respectively. Umbilical cord gases were as follows: venous pH 7.29 and arterial pH 7.03 with a bicarbonate of 15.3 mmol/liter. He was an appropriately grown infant without anomalies. His vital signs became progressively more unstable throughout the day with hypotension, cyanosis, and the eventual development of intractable metabolic acidosis. Echocardiogram showed pulmonary hypertension without evidence of structural heart disease. Chest radiographs showed homogeneous alveolar densities. Management included antibiotics (ampicillin and gentamycin), intravenous immunoglobulin, fresh frozen plasma, dopamine, and high-frequency jet ventilation. Despite this management, he died at 15 hours of age. Spun hematocrits revealed evidence of intravascular hemolysis with the serum being red. Blood culture eventually returned as positive for Clostridium perfringens and
These two infants with congenital sepsis presented with clinical findings strongly suggestive of overwhelming Clostridial infection. Although no culture results were obtained to substantiate the diagnosis in case 1, the histologic findings of grampositive and gram-variable bacilli with subterminal spores strongly implicate Clostridia as being the etiology. The clinical findings of obtundation, shock, and intravascular hemolysis that were seen in both cases have been well described with Clostridial infection, primarily in the clinical setting of gas gangrene. This presentation is generally believed to be due to the elaboration of exotoxin, especially a phospholipase, alpha toxin. This most often accompanies a localized infection of devitalized tissue and can result in cardiovascular collapse and death before a bacteremia is evident.9 The presentation of Clostridial infection in these infants was rather unusual in that there was no obvious devitalized tissue to support the origin of an anaerobic infection. Both infants, however, were premature and were born to mothers with the clinical diagnosis of chorioamnionitis, a diagnosis later confirmed by histologic examination of the placenta. Anaerobic bacteria are commonly associated with chorioamnionitis3 and are generally of low virulence. Infants born to mothers with chorioamnionitis due to anaerobic infection generally do well. Since both of the mothers had been hospitalized prior to their deliveries, it is possible that the Clostridial organisms were introduced iatrogenically. More likely, the infection and rapid death of these infants were unfortunate complications of chorioamnionitis in infants who were relatively immune deficient because of their prematurity. On review of the literature, only four other cases of congenital Clostridial sepsis could be identified (Table I). 41 !-13 This may be an underestimate of the prevalence of this infection, since some infants (especially those born prematurely) likely die before accurate diagnosis can be made. Interestingly, two of the reported cases describe systemic infections involving both mother and infant. Both of these infants were delivered by emergency cesarean section and maternal morbidity was related, at least in part, to involvement of the surgical wound. The relatively benign postpartum course of the two mothers presented herein is likely related to the avoidance of cesarean delivery. Including the historical cases where clinical information is provided, there are several common 371
Downloaded by: National University of Singapore. Copyrighted material.
DISCUSSION
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 8, NUMBER 6
Congenital Sepsis Due to Clostridia spp.
Isolated
Chowetal (1974) Chaney (1980) Akonkhai et al (1981) Orzel etal (1983) Gallaher and Marks (1991)
Blood Maternal blood, infant blood Placenta, blood Placenta, maternal blood, gastric aspirate Blood Placenta, lungs
perinatal factors; however, none of these are unique for Clostridial infection. The majority of the cases (four of five) presented with chorioamnionitis. Evidence of fetal distress (four offive)and premature or prolonged rupture of the membranes (three of five) were also noted. Premature birth has only been described in the two infants in this report. The clinical manifestations are similar to those described for typical cases of gas gangrene.9 Evidence of intravascular hemolysis, respiratory distress, and disseminated intravascular coagulopathy were seen in the majority of the cases reported. Clostridium spp are very susceptible to treatment with penicillin. Since in the cases reviewed devitalized tissue was not a source of infection, the value of adjunctive treatments such as hyperbaric oxygen seems small. If as suggested by Orzel et al11 the placenta, membranes, or amniotic fluid are the sources of infection, then the source would be removed by delivery. The overall mortality in this series of congenital Clostridial sepsis is two of six (33%), with both deaths occurring in the prematurely born infants described herein. Interestingly, the infant reported by Orzel et al survived after undergoing an exchange transfusion. Since much of the systemic illness is toxin mediated, perhaps the combination of antibiotics and exchange transfusion resulted in a more rapid removal of systemic exotoxin. The first step in adequate treatment of an illness is its rapid clinical recognition. Physicians caring for infants in the immediate postnatal period need to be aware that fulminant sepsis with intravascular hemolysis may be due to Clostridial infection. Although two thirds of the infants reported herein survived, it is possible that the most severely ill infants die undiagnosed and unreported. This infection appears to be especially devastating in the prematurely born infant. In this situation, it is interesting to speculate whether supportive therapy such as exchange trans-
372
Outcome
Lived Lived Lived Lived Died Died
Type
C. C. C. C. C.
perfringens perfringens perfringens perfringens perfringens —
fusion aimed at removing the exotoxin may improve outcome over systemic antibiotics alone. REFERENCES 1. Kelsall GRH, Barter RA, Manessis C: Prospective bacteriological studies in inflammation of the placenta, cord, and membranes. J Obstet Gynaecol Br Commonw 74: 401-411, 1967 2. Gorbach SL, Thadepalli M: Isolation of Clostridium in human infections. J Infect Dis 131:S81-S85, 1975 3. Pankuch GA, et al: Placental microbiology and histology and the pathogenesis of chorioamnionitis. Obstet Gynecol 64:802-806, 1984 4. Chow AW, Leake RD, Yamanchi T, Anthony BF, Guze LB: The significance of anaerobes in neonatal bacteremia: Analysis of 23 cases and review of the literature. Pediatrics 54:736-745, 1974 5. Long JG, Preblud SR, Keyserling HL: Clostridium perfringens meningitis in an infant; case report and literature review. Pediatr Infec Dis 6:752-754, 1987 6. Freedman S, Hollander M: Clostridium perfringens septicemia as a postoperative complication of the newborn infant. J Pediatr 71:576-578, 1967 7. Isenberg AN: Clostridium welchii infection: A clinical evaluation. Arch Surg 92:727-731, 1966 8. Bogdan JC, Rapkin RH: Clostridia infection in the newborn. Pediatrics 58:120-122, 1976 9. Stunden RJ, Brown RA, Rode H, Millar AJW, Cywes S: Umbilical gangrene in the newborn. J Pediatr Surg 23: 130-134, 1988 10. Walker SH, Macaraeg El: Neonatal sepsis due to Clostridium perfringens. Md State Med J 22:61-62, 1973 11. Orzel JA, Cohen DL, McDonald EC, Gandy G: Clostridium perfringens sepsis involving mother and neonate with survival of both. Pediatr Infect Dis 2:457-459, 1983 12. Chaney NE: Clostridium infection in mother and infant. Am J Dis Child 134:1175-1176, 1980 13. Ahonkhai, VI, Kim MH, Raziuddin K, et al: Perinatal Clostridium perfringens infection. Clin Pediatr (Phila) 20:532-533,1981
Keith J. Gallaher is the recipient of National Research Service Award HL07589.
Downloaded by: National University of Singapore. Copyrighted material.
Table 1.
November 1991
![[Therapy-refractory fulminant meningococcal sepsis].](/assets/img/hold.png)
