This is a 3200 g term newborn female delivered via normal spontaneous vaginal delivery to a 25 year old G1P0 syphilis non-reactive, group B strep (GBS) negative, rubella immune, hepatitis B surface antigen negative mother with early preeclampsia and thrombocytopenia (platelet count 80,000). Rupture of membranes occurred 11 hours prior to delivery with clear fluid. Intrapartum medications included 3 doses of butorphanol (narcotic opioid analgesic). The last dose was administered within 1 hr of delivery. There was no maternal fever. Apgars were 8 and 9.

In the newborn nursery, vital signs are: HR 140, T 37, BP 47/39, RR 54. Oxygen saturation is 98-100% in room air. The infant appears slightly pale and mottled. She is centrally pink with persistent grunting, shallow respirations, and lethargy. Her fontanelle is soft and flat. Heart exam is normal. Lungs show good aeration. Abdomen is soft and without masses. Pulses are 1+ throughout with 3-4 sec capillary refill. Neuro exam shows decreased tone and a weak, intermittent cry.

Labs: CBC with WBC 3,200, 6% segs, 14% bands, 76% lymphocytes, Hgb 15, Hct 43, platelets 168,000. Blood glucose 52. The chest x-ray is rotated with fluid in the right fissure, diffuse streakiness on the left, and a normal cardiac silhouette. CBG (capillary blood gas) pH 7.31, pCO2 43, pO2 44, BE-4. CSF: 2430 RBCs, 20 WBCs, 1% PMN, 17% lymphs, 82% monos, glucose 39, protein 133, gram stain shows no organisms.

You are asked to consult on this case. What other tests would you obtain? What would your assessment be for this infant? What would your recommendations be (if any) for further evaluation or treatment? If you were to treat this infant, how long would you treat her?

The evaluation and management of the neonate at risk for sepsis is potentially a source of frustration for students and practitioners. The convention in the past has often been to evaluate and empirically treat all neonates felt to be at significant risk, especially as relates to maternal factors and the receipt of maternal antibiotics in labor. Due to evolutions in health care and the advent of intrapartum prophylaxis for group B streptococcal sepsis (mothers are routinely screened for group B strep and if found to be positive, they are given ampicillin prior to delivery), more attention has come to focus (very appropriately) on the clinical evaluation of the infant as a major part of the decision to evaluate and treat with antibiotics. This factor; however, remains fraught with a degree of uncertainty related to the nonspecific manifestations of infection in the newborn, the sometimes rapid progression of sepsis in the newborn, and the lack of laboratory tools which have high positive predictive accuracy.

The approach in this section of neonatal sepsis will be to: 1) incorporate the evolutionary changes in management which are based on more recent evidence; 2) to emphasize the lack of a gold standard underlying the variations in practice (i.e., clinical sepsis with a negative blood culture is still more often diagnosed than blood culture proven sepsis); and 3) to suggest (based on interpretation of older and recent evidence) newer concepts which place more reliance on tests with high negative predictive accuracy and the efficacy of intrapartum antibiotics (1-7).

The information upon which former standard practice is based is also provided throughout the chapter. These are necessary and basic to understanding the problem of neonatal sepsis and perinatal infections. However, the evaluation and management will de-emphasize empiric treatment for risk alone, and variation in practice will be seen as a necessary consequence of our lack of knowledge and the inherent variation in individual practitioner's tolerance of degree of risk and uncertainty.

Table 1. Common bacterial and viral infectious agents causing sepsis (or something similar to sepsis):
. . . . E. Coli
. . . . Group B streptococcus (GBS)
. . . . Listeria monocytogenes
. . . . Herpes simplex
. . . . Cytomegalovirus
. . . . Any virus infecting the mother in the week prior to delivery any bacteria cultured from the mother on admission for labor

Table 2. High risk factors for neonatal sepsis:
. . . . Late maternal prenatal care
. . . . Maternal UTI, STD, or abnormal serologies
. . . . Prolonged rupture of membranes (>24 hrs)
. . . . Maternal fever prior to delivery
. . . . Maternal chorioamnionitis
. . . . Prematurity
. . . . GBS positive screen without intrapartum prophylaxis

Table 3. Signs and symptoms of neonatal infection (most are NONSPECIFIC):
. . . . Apnea and dusky episodes for no clear reason.
. . . . Lethargy, poor color, hypoactivity, poor capillary refill.
. . . . Feeding intolerance (more than usual spit-up), abdominal distention.
. . . . Clinical appearance; doesn't look "good".
. . . . Tachypnea, temperature instability, look of distress.

Table 4. The most important risk factors for neonatal sepsis:
. . . . Prematurity
. . . . Untreated maternal chorioamnionitis.
. . . . Untreated maternal prolonged rupture of membranes.
. . . . Maternal fever, untreated.
. . . . Untreated positive maternal GBS screen.

Table 5. Equivocal risk factors (i.e., they overlap or may result in similar manifestations):
. . . . Fetal distress.
. . . . Depression at birth (needs resuscitation, low 5 minute Apgar).
. . . . Meconium staining.
. . . . Hypoglycemia.
. . . . Any unusual finding which may be due to infection.

Although we have gained more knowledge about risk factors and have more antibiotics at our disposal, there is still NO GOLD STANDARD for the diagnosis of neonatal infection. There are still many unknowns in neonatal sepsis which continue to elude us, and compel the diagnosis of neonatal infection to be made clinically more often than not.

Table 6. The Unknowns in Neonatal Sepsis:
. . . . 1. How effective is GBS prophylaxis as prescribed? >95%
. . . . 2. How sensitive are blood cultures (i.e., how often are they positive) ?
. . . . 3. Can an elevated l/T ratio (immature to total granulocyte ratio) indicate acute OR resolving inflammatory response?
. . . . 4. Will ampicillin resistant organisms be seen with more use of intrapartum ampicillin prophylaxis?
. . . . 5. What is the minimum duration of antibiotic treatment to effectively treat sepsis?
. . . . 6. Is neonatal infection with a positive blood culture the same as neonatal sepsis?
. . . . 7. When does neonatal sepsis become SIRS (systemic inflammatory response syndrome), i.e., overwhelming sepsis?
. . . . 8. What is the immunologic competence level of a given infant at risk (i.e., will the infant be able to respond positively with appropriate antibiotics)?
. . . . 9. Does intrapartum treatment of the mother for chorioamnionitis also treat the fetus effectively?

Because we have many unknowns and the worst case scenario for neonatal infection is sepsis and perhaps overwhelming sepsis or death from SIRS, pediatricians have tended to err on being conservative in the evaluation for sepsis. This intention paradoxically results in a more "aggressive" approach to the patient in terms of tests and/or treatment. This paradox is underscored by the lack of a gold standard for diagnosing sepsis in the newborn, and complicated by the recent increase of intrapartum antibiotics prescribed to women in labor.

Table 7. The full sepsis work-up.
. . . . 1. CBC differential, platelet count.
. . . . 2. Blood, urine, and CSF cultures.
. . . . 3. CXR. Add a tracheal aspirate for gram stain and culture if the patient is intubated.
. . . . 4. Equivocal: gastric aspirate for gram stain and culture.
. . . . 5. Start broad spectrum antibiotics while awaiting culture results.

For a partial sepsis work-up, one could pick any one or more of the above items. For a totally asymptomatic infant with high risk factors, none of the steps might be elected (practice variation). This is based on the premise that the clinical appearance and serial monitoring of the infant is just as accurate as any laboratory test for indicating the presence of infection, given any set of risk factors in an infant with a relatively normal exam.

This wide variation of practice suggests that the unknowns in neonatal sepsis (see above) are quite important to practical management. This may lead one to be more or less restrictive in practice, and requires one to have thorough knowledge of the predictive accuracy of the objective tools available in the assessment of neonatal sepsis. From an outcomes point of view, one would expect that if certain practices were inappropriate, there would be a higher rate of readmission within two weeks of discharge from the normal nursery for those regimens which were "least restrictive." Such evidence has not emerged from this institution, based on a review of early discharge from the nursery in the mid-1990's, when the most common cause for readmission was jaundice (infection and sepsis were not found).

The highest degree of controversy surrounds the group of infants who are asymptomatic with some risk factors for sepsis, especially those whose mothers received intrapartum antibiotics. In these infants, there is the fear of partially treated sepsis, prompting evaluation and treatment of these infants based on their risk factors and discounting the maternal antibiotics. However, the asymptomatic state could also be interpreted as adequate prophylactic treatment for neonatal bacteremia. In 1990, Wiswell et al., reported on a survey of academic infectious disease departments with respect to management of this scenario. They concluded that there is no consensus regarding management of pretreated, healthy appearing, term gestation neonates (8). In contrast, Teji et al (1994) surveyed neonatologists in Midwestern states of the U.S. with regard to the management of PROM (prolonged rupture of membranes) without chorioamnionitis, chorioamnionitis without treatment prior to delivery, and chorioamnionitis with treatment prior to delivery. One hundred thirty seven responses were received and prematurity and severity of maternal illness significantly influenced the decision to treat empirically, irrespective of screening test results (9). More recently, Eichenwald (1997) has suggested a very reasonable scheme for evaluation of the asymptomatic term infant, based on a protocol developed by the Joint Program in Neonatology in Boston (Table 8) (10). However, the question persists and evolves regarding the benefits and risks of routine therapy of high risk neonates vs. clinical observation and selective therapy of only those infants who manifest symptoms. This evolution is highlighted by the recent reports of ampicillin-resistant organisms in neonatal sepsis (11-13) and the dramatically increased incidence of Candida species sepsis in very premature infants in NICU settings over the last decade, of which one very important contributor is the prior use of antibiotics.

Table 8. Management of asymptomatic term infants with risk factors for infection for term, well appearing infants with maternal antibiotics given in labor.
. . . . Tests: CBC, differential, platelet count, blood culture (volume of blood is important; 1cc recommended).
. . . . Antibiotics until 48 hour blood culture results are available if:
. . . . . . . 1. I/T>0.2 (immature neutrophils to total neutrophil ratio) or
. . . . . . . 2. WBC <5000 or
. . . . . . . 3. Mother received antibiotics for suspected or diagnosed chorioamnionitis.
. . . . . . . 4. GBS positive mother, adequately treated, but with a history of a previously affected infant with invasive GBS infection

In this scenario, the availability of rapidly available tests with high negative predictive accuracy would seem particularly useful. Several fitting this category are:
. . . . 1. The total WBC and l/T ratio (14)
. . . . 2. Serial CBC's using total WBC and l/T ratio (15)
. . . . 3. A hematologic scoring system (16)
. . . . 4. A combination of CRP and IL-6 (17)

Singhal and La Gamma (1996) in a study of 6620 pregnancies, found that 82% of at-risk patients are asymptomatic and have negative body fluid cultures. They concluded that their data support restricting a full course of antibiotic treatment to only those patients with clinical or laboratory signs of sepsis (18%) (5). Escobar et al (2000) reported on a large population of newborns in the Kaiser system of whom 15% were evaluated for sepsis (4). Only 2.2% met criteria for proven, probable, or possible bacterial infection, and of those meeting criteria, 0.8% had positive cultures while 1.4% had clinical evidence of bacterial infection. 1568 out of 2785 infants evaluated were not treated, and the initial asymptomatic status was associated with a decreased risk of infection (adjusted odds ratio; AOR=0.26). Factors associated with increased AOR for infection were chorioamnionitis, low absolute neutrophil count, and meconium stained amniotic fluid. They concluded that evidence based observation and treatment protocols could be defined, based on a limited set of predictors: maternal fever, chorioamnionitis, initial neonatal examination, and absolute neutrophil count (4). Ultimately, each practitioner must determine the degree of risk or uncertainty that he or she can accept on the basis of clinical and institutional experience.

Table 9. A revised and composite screen and evaluation for sepsis in the neonate.
. . . . Risk factors: Prematurity, chorioamnionitis, prolonged rupture of membranes, maternal fever, fetal tachycardia and depression at birth.
. . . . Screening tests: CBC and differential and platelet count; total WBC and I/T ratio (initial and serial); blood culture; urine culture or GBS antigen; others as may be available to increase negative predictive accuracy such as CRP, IL-6; clinical exam of the infant.
. . . . Completing the evaluation: Lumbar puncture for CSF studies and culture; CXR and/or endotracheal aspirate for gram stain and culture.
. . . . Treatment: Institute broad spectrum antibiotic coverage for neonatal sepsis. If meningitis is suspected, add cefotaxime to the regimen.
. . . . For premature infants in whom the physical exam may be more equivocal and whose prematurity constitutes an additional risk factor, the threshold for a full sepsis evaluation and antibiotic treatment is much lower.

Table 10. Rates of infection in neonates and mortality rates.
. . . . Proven sepsis: 2.5 per 1000 live births, mortality 8.7% (18).
. . . . Clinical sepsis: 3.6 per 1000 live births, mortality 4.3% (18).
. . . . VLBW (very low birth weight) proven sepsis: 26.5 per 1000 live births (18).
. . . . VLBW clinical sepsis: 32.4 per 1000 live births (18).
. . . . EOGBS (early onset GBS) 0.5 per 1000 live births, mortality 10% (19).
. . . . Other early onset infection 0.5 per 1000 live births (19).

Questions

1. For the case presented at the beginning of this chapter, you are asked to consult on this case. What other tests would you obtain?

2. What would your clinical assessment of this infant be?

3. What would your recommendations for further evaluation and/or treatment be?

4. If you were to treat this infant, how long would you treat?

5. What tests have the highest positive predictive accuracy in neonatal sepsis?

6. What tests have the highest negative predictive accuracy in neonatal sepsis?

7. Is the volume of blood obtained for the blood culture important to the culture being positive or negative?

8. Is there good evidence that treatment of maternal chorioamnionitis prior to delivery significantly reduces the risk of neonatal infection?

9. Does prophylaxis for group B strep infection alter the time course of early onset group B streptococcal sepsis if prophylaxis is ineffective?

10. What is the incidence of neonatal sepsis and what is the mortality from neonatal sepsis?

References

1. Gibbs KS, Dinsmoor MJ, et al. A randomized trial of intrapartum antibiotic prophylaxis vs. immediate postpartum treatment of women with intra-amniotic infection. Obstet Gynecol 1988;72:823-828.

2. Sperling KS, Ramamurthy KS, Gibbs KS. A comparison of intrapartum vs. immediate postpartum treatment of intra-amniotic infection. Obstet Gynecol 1987;70:861-865.

3. Mecredy RL, Wiswell TF, Hume KF. Outcome of term gestation neonates whose mothers received intrapartum antibiotics for suspected chorioamnionitis. Am J Perinatol 1993; 10:365-8.

4. Escobar GJ, Li DK, et al. Neonatal sepsis workups in infants >/=2000 grams at birth: A population based study. Pediatrics 2000;106(2 Pt 1):256-263.

5. Singhal KK, La Gamma EF. Management of 168 neonates weighing more than 2000 g receiving intrapartum chemoprophylaxis for chorioamnionitis. Evaluation of an early discharge strategy. Arch Pediatr Adolesc Med 1996;150:158-163.

6. Cararach V, Botet F, et al. Administration of antibiotics to patients with rupture of membranes at term: a prospective, randomized, multicentric study. Collaborative Group on PROM. Acta Obstet Gynecol Scand 1998;77:298-302.

7. Schrag SJ, Zywicki S, et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis. N Engl J Med 2000;342:15-20.

8. Wiswell TE, Stoll BJ, Tuggle JM. Management of asymptomatic, term gestation neonates born to mothers treated with intrapartum antibiotics. Pediatr Infect Dis J 1990;9:826-831.

9. Teji JS, Srinivasan G, et al. Management of asymptomatic neonates with prolonged rupture of membranes. Indian J Pediatr 1994;61:63-69.

10. Eichenwald EC. Perinatally transmitted neonatal bacterial infections. Inf Dis Clin North Am 1997;11:223-239.

11. Levine EM, Ghai V, et al. Intrapartum antibiotic prophylaxis increases the incidence of gram-negative neonatal sepsis. Infect Dis Obstet Gynecol 1999;7:210-213.

12. Mercer BM, Carr TL, et al. Antibiotic use in pregnancy and drug-resistant infant sepsis. Am J Obstet Gynecol 1999;181:816-821.

13. Schuchat A, Zywicki SS, et al. Risk factors and opportunities for prevention of early-onset neonatal sepsis: a multicenter case-control study. Pediatrics 2000;105(1 Pt l):21-26.

14. Sinclair J. Early diagnosis of neonatal sepsis. Yearbook of Pediatrics 1982:11-13.

15. Greenberg DN, Yoder BA. Changes the differential white blood cell count in screening for group B streptococcal sepsis. Pediatr Infect Dis J 1990;9:886-889.

16. Rodwell RL, Leslie AL, Tudehope DI. Early diagnosis of neonatal sepsis using a hematologic scoring system. J Pediatr 1988;112:761-767.

17. Doellner H, Arntzen KJ, et al. Interleukin-6 concentrations in neonates evaluated for sepsis. J Pediatr 1998;132:295-299.

18. Lopez Sastre JB, Coto Cotallo GD, et al. Neonatal sepsis of vertical transmission: an epidemiological study from the "Grupo de Hospitales Castrillo." J Perinat Med 2000;28:309-315.

19. Isaacs D, Royle JA. Intrapartum antibiotics and early onset neonatal sepsis caused by group B streptococcus and other organisms in Australia. Australasian Study Group for Neonatal Infections. Pediatr Infect Dis J 1999;18:524-528.

20. Bromberger P, Lawrence JM, et al. The influence of intrapartum antibiotics on the clinical spectrum of early onset group B streptococcal infection in term infants. Pediatrics 2000;106:244-250.

Answers to questions

1. Blood and urine cultures, if not already done.

2. Clinical sepsis with poor perfusion and neutropenia; possible septic shock with narrow pulse pressure.

3. a) Repeat CBC to monitor the neutropenia and thrombocytopenia. b) Volume bolus to improve perfusion. c) Follow-up exam of abnormal tone and cry after instituting supportive therapy. d) Start broad spectrum antibiotics parenterally. e) Transfer from the normal nursery to a higher level nursery or intensive are unit for continuous monitoring of vital signs.

4. Seven to ten days empirically, given the clinical presentation and depending on culture results. Serial CRPs may also be used to assist with duration of treatment.

5. Any 2 from the battery reviewed by Sinclair (14) gave 62% for sepsis proved or probable.

6. Again any 2 from the above reference (14) gives 98% negative predictive accuracy for sepsis proved or probable. However, the CBC and differential alone will give you two out of this battery.

7. Yes. At least one ml should be obtained for blood cultures.

8. Yes

9. No. This has implications for the current AAP protocol for monitoring infants whose mothers did not receive prophylaxis.

10. 2.5 per 1000 live births, with mortality rate of 8.7% (18). Clinical sepsis is cited as 3.6 per 1000 live births with mortality of 4.3%. Figures are much higher for VLBW infants.