Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants

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Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants Gil Klinger, MD; Itzhak Levy, MD; Lea Sirota, MD; Valentina Boyko, MSc; Brian Reichman, MBChB; Liat Lerner-Geva, MD; in collaboration with the Israel Neonatal Network OBJECTIVE: The purpose of this study was to determine the incidence,

causative pathogens, and risk factors for early onset sepsis (EOS) among very-low-birthweight (VLBW) infants. STUDY DESIGN: This was a population based observational study.

Data were prospectively collected by the Israel Neonatal Network between 1995 and 2005. Multivariable analyses identified independent risk factors for EOS.

membrane rupture ⬎ 24 hours without amnionitis (OR, 2.10; 95% CI, 1.53-2.88), amnionitis with membrane rupture ⬍ 24 hours (OR, 4.28; 95% CI, 2.97-6.16), and amnionitis with membrane rupture ⱖ 24 hours (OR, 8.15; 95% CI, 5.98-11.10) were associated with EOS, but not antenatal steroids or gestational age. CONCLUSION: EOS was caused mainly by gram-negative bacteria.

RESULTS: EOS developed in 383 of 15,839 infants (2.42%). Fifty-five

Prolonged rupture of membranes and amnionitis have an additive effect on EOS with an above 8-fold excess risk when both were present.

percent of pathogens isolated were gram-negative bacteria. Lack of prenatal care (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.32-2.86), delivery room resuscitation (OR, 2.49; 95% CI, 1.91-3.24),

Key words: amnionitis, early onset sepsis, prolonged rupture of membranes, risk factors, very-low-birthweight infant

Cite this article as: Klinger G, Levy I, Sirota L, et al. Epidemiology and risk factors for early onset sepsis among very-low-birthweight infants. Am J Obstet Gynecol 2009;201:38.e1-6.

E

arly onset sepsis (EOS) is a serious problem among very-low-birth weight (VLBW) infants that is associated From the Department of Neonatal Intensive Care (Drs Klinger and Sirota) and the Infectious Disease Unit (Dr Levy), Schneider Children’s Medical Center of Israel, Petah Tiqva; the Women and Children’s Health Research Unit (Ms Boyko, Drs Reichman and Lerner-Geva), Gertner Institute, Chaim Sheba Medical Center, Tel Hashomer; and Departments of Pediatrics (Drs Klinger, Levy, Sirota, Reichman) and Epidemiology (Dr Lerner-Geva), the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Presented at the Joint Meeting of the Pediatric Academic Societies and the Asian Society for Pediatric Research, Honolulu, HI, May 2-6, 2008. Received Nov. 8, 2008; revised Jan. 7, 2009; accepted March 4, 2009. Reprints: Gil Klinger, MD, Department of Neonatology, Schneider Children’s Medical Center of Israel, 14 Kaplan St., Petah Tiqva, 49202, Israel. [email protected]. The Israel National VLBW infant database is partially funded by the Israel Center for Disease Control and the Israel Ministry of Health. 0002-9378/$36.00 © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.03.006

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with a threefold increased risk of mortality.1 The incidence of EOS is 15-19 per 1000 live births of VLBW infants,2-4 and has remained stable despite a shift in the causative pathogens of EOS from a predominance of Group B Streptococci (GBS) to that of Escherichia coli.1-3 The risk of EOS in the newborn is inversely related to birthweight (BW), degree of prematurity, and socioeconomic status, and is increased following rupture of membranes for more than 24 hours or in the presence of maternal peripartum infection.4,5 Risk factors for EOS in VLBW infants may differ from those found in term infants. A small cohort study in VLBW infants has found that predictive factors for EOS diagnosed within 24 hours after birth were chorioamnionitis and advanced maternal age.6 A recent cross-sectional study has found similar findings and has also suggested that multiparous women, multiple courses of prenatal steroids, use of tocolytic agents, premature rupture of membranes, and low gestational age (GA) were all associated with EOS.7 The objectives of this populationbased study were to determine the inci-

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dence, the causative pathogens, and risk factors for EOS in VLBW infants.

M ATERIALS AND M ETHODS This population-based observational study was performed on data obtained from the Israel National VLBW Infant Database (Appendix). This study was approved by the Human Research Committee of the Sheba Medical Center.

The Israel National VLBW Infant Database Data were prospectively collected by the Israel Neonatal Network on VLBW newborn infants (BW ⱕ 1500 g) born in Israel from 1995 through 2005. All 28 neonatal departments in Israel participated in the data collection as previously described.8 Data collected included demographic details, antenatal and perinatal history, postdelivery status and neonatal diagnoses, medical and surgical treatments, and outcome at discharge. A prestructured form was completed for each infant, checked for logic errors and, if necessary, returned to the participating center for clarification. Interhospital transfers were followed by the database coordinator until final discharge home.

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TABLE 1

Distribution of pathogens among very-lowbirthweight infants with early onset sepsis Pathogens Gram-positive bacteria

n (%) Coagulase negative Staphylococci

68 (17.2%)

Group B Streptococci

37 (9.4%)

Streptococcus viridans

26 (6.6%)

Listeria

12 (3.0%)

Enterococci

11 (2.8%)

Staphylococcus aureus

10 (2.5%)

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

Streptococcus pneumonia

2 (0.5%)

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

All gram-positive bacteria

166 (42%)

Escherichia coli

106 (26.8%)

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

Gram-negative bacteria

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

Klebsiella

27 (6.8%)

Hemophilus

16 (4.1%)

Enterobacteria

13 (3.3%)

Pseudomonas

12 (3%)

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

Bacteriodes

9 (2.3%)

Citrobacter

9 (2.3%)

Acinetobacter

8 (2.0%)

Morganella

5 (1.3%)

Proteus

4 (1.0%)

Serratia

3 (0.8%)

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

Other gram-negative bacteria

6 (1.5%)

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

All gram-negative bacteria

218 (55%)

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

Yeasts

Candida

11 (2.8%)

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

All pathogens

395 (100%)

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

Klinger. Epidemiology and risk factors for early onset sepsis. Am J Obstet Gynecol 2009.

All departments used an operating manual and standard definitions based on those of the Vermont-Oxford Trials Network.9 Data were collected on all infants until death or discharge home.

Study population From 1995 through 2005, the database included records of 16,462 infants, which comprised more than 99% of all live births of VLBW infants in Israel. Excluded from analysis were 623 infants who died in the delivery room or from lethal malformations. The remaining 15,839 infants comprised the study population. Definitions The GA in completed weeks was defined as the best estimate of GA based on last

menstrual period, obstetric history and examination, prenatal ultrasound, or early postnatal physical examination. Small for gestational age (SGA) was defined as a BW below the 10th percentile for GA according to the gender specific growth charts of Kramer et al.10 Prolonged rupture of membranes (PROM) was considered as rupture of membranes for more than 12 hours before delivery. The diagnosis of amnionitis was based on maternal fever (⬎ 37.8°C orally or ⬎ 38.0°C rectally) recorded twice in 1 hour, during membrane rupture or within 6 hours after delivery providing no other cause for fever was found.11 Bacteriological confirmation of amnionitis was not required. Antenatal steroid therapy included infants receiving partial or com-

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plete courses of therapy. EOS was defined on the basis of a positive blood culture obtained within the first 72 hours of life.1 Cultures positive for organisms considered contaminants (Corynbacterium, Proprionobacterium, diphtheroids, or Micrococcus) were not considered as EOS. The diagnosis of coagulase negative Staphylococcal (CONS) sepsis was determined according to the criteria of the Vermont Oxford Network Database,8,9 and required clinical signs of sepsis including apnea, temperature instability, feeding intolerance, worsening respiratory distress or hemodynamic instability, a positive blood culture, and antibiotic treatment for at least 5 days or until death.

Statistical analysis The association between EOS and perinatal and neonatal factors was tested using the ␹2 test for categorical variables and the 2-sample t test test for continuous variables. For infants with PROM, analyses were performed in strata according to duration of membrane rupture. Multivariable analyses were used to identify the independent effect of each variable on EOS adjusted for other risk factors. To account for the possible interaction between the duration of rupture of membranes (ROM) and amnionitis and to identify the independent effect of each variable, the following combinations were considered: ROM ⬍ 12 hours ⫹ no amnionitis, ROM of 12-23 hours ⫹ no amnionitis, ROM ⱖ 24 hours ⫹ no amnionitis, ROM ⬍ 24 hours ⫹ amnionitis, ROM ⱖ 24 hours ⫹ amnionitis. Multivariable analyses are presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Although CONS were considered causative organisms, separate analyses were performed with and without these organisms since some may represent contaminants. Statistical analyses were performed using the SAS statistical software, version 9 (SAS Institute, Inc, Cary, NC).

R ESULTS The study cohort comprised 15839 infants of whom 383 (2.42%) had EOS. In infants with EOS, 404 pathogens were isolated, 9 of which were considered con-

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TABLE 2

Antenatal and perinatal characteristics of very-low-birthweight infants with and without early onset sepsis Characteristic Mean maternal age (y) (⫾SD)

Early onset sepsis (n ⴝ 383) 29.8 (⫾6.1)

No early onset sepsis (n ⴝ 15,456) 29.4 (⫾5.9)

P value .01

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

Jewish ethnicity

292 (76.4%)

11,258 (73.0%)

.13

No antenatal care

35 (9.1%)

823 (5.3%)

Fertility treatment

103 (27.1%)

5315 (34.6%)

Multiparity

129 (31.3%)

6683 (43.2%)

⬍ .0001

Antenatal steroid therapy—any

251 (64.1%)

9875 (65.9%)

.45

62 (16.2%)

4850 (31.4%)

⬍ .0001

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

.002

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

.002

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

Small for gestational age

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

Maternal hypertensive disorders

43 (11.3%)

3113 (20.2%)

⬍ .0001

2207 (59.6%)

8709 (56.4%)

.22

57 (15.1%)

2408 (15.6%)

.78

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

Premature contractions

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

Antepartum hemorrhage

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

⬍ .0001

Duration of rupture of membranes

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

0-11 h

214 (58.0%)

12-23 h

10 (2.7%)

12,482 (82.1%) 439 (2.9%)

ⱖ 24 h

145 (39.3%)

2271 (15.0%)

Amnionitis

126 (33.4%)

1055 (6.8%)

Cesarean delivery

226 (59.0%)

10,681 (69.1%)

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

⬍ .0001

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

⬍ .0001

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

Mean gestational age (wk) (⫾SD)

27.7 (⫾2.6)

29.1 (⫾3.0)

⬍ .0001

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

1005 (⫾287)

1102 (⫾283)

⬍ .0001

Male gender

205 (53.5%)

7843 (50.8%)

.28

Delivery room resuscitation

272 (71.0%)

6679 (43.2%)

Mean birthweight (g) (⫾SD)

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

⬍ .0001

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

Mean 5-min Apgar score (⫾SD)

7.6 (⫾2.1)

8.5 (⫾1.7)

⬍ .0001

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

Klinger. Epidemiology and risk factors for early onset sepsis. Am J Obstet Gynecol 2009.

taminants, leaving 395 pathogens available for analysis (Table 1). Three hundred eighty-three infants were diagnosed with EOS (in 12 infants 2 different pathogens were isolated). Gram-negative bacteria were the most common pathogens with E coli responsible for 26.8% of the episodes of EOS. Only 9.4% of all episodes of EOS were caused by GBS. The antenatal and perinatal characteristics of VLBW infants with and without EOS are presented in Table 2. VLBW infants with EOS were more likely to have not received antenatal care (5.3% vs 9.1%; P ⫽ .002), to be born following PROM (42.0% vs 17.9%; P ⬍ .0001), to be of a lower mean BW (1005 g vs 1102 g; P ⬍ .0001) and of a lower mean GA (27.7 wk vs 29.1 wk; P ⬍ .0001), and to have required resuscitation after delivery (71.0% vs 43.2%; P ⬍ .0001). 38.e3

An increased rate of EOS was identified when duration of ROM was 24 hours or more (Figure 1). The percent of infants with EOS following ROM ⬍ 24 hours was 1.7% compared to 6.0% following ROM ⱖ 24 hours (P ⬍ .0001). Increased ROM duration beyond 36 hours did not further increase the rate of EOS. The effect of duration of ROM and amnionitis on the rate of EOS is presented in Figure 2. The rate of EOS was only 1.4% when both ROM ⱖ 24 hours and amnionitis were absent, but increased to 13.3% when both factors were present. ROM ⱖ 24 hours and/or amnionitis were present in 203 of 383 infants with EOS (53.0%). Multivariable analyses of perinatal variables associated with EOS are presented in Table 3. The analyses are reported for the complete cohort of infants with EOS as well as for the cohort of in-

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fants with EOS excluding infants in whom the causative organism was CONS. For the complete cohort, EOS was associated with an increased risk of not receiving antenatal care (OR, 1.94; 95% CI, 1.32-2.86) or requiring delivery room resuscitation (OR, 2.49; 95% CI, 1.91-3.24). An 8-fold excess risk for EOS was identified when both ROM ⱖ 24 hours and amnionitis were present vs when absent. EOS was not associated with antenatal steroid use, ROM duration of 12-23 hours in the absence of amnionitis, premature contractions, or delivery mode. Similar results occurred in the analysis that excluded infants with CONS sepsis.

C OMMENT The incidence of EOS was 2.4% in a near-complete national Israeli cohort of VLBW infants. Episodes of EOS were

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FIGURE 1

Percent of VLBW infants with early onset sepsis by duration of membrane rupture

The histogram shows the relationship between duration of membrane rupture and the risk of early onset sepsis. Klinger. Epidemiology and risk factors for early onset sepsis. Am J Obstet Gynecol 2009.

caused predominantly by gram-negative organisms. EOS was independently associated with lack of antenatal care, delivery room resuscitation, PROM and amnionitis, and was not associated with antenatal steroid use, premature contractions, or GA. The most common organisms causing EOS were gram-negative bacteria, similar to reports by the NICHD network.1,2 GBS was isolated in less than 10% of EOS episodes. This was likely influenced by

both the relatively low rate of GBS colonization in Israeli women estimated at 1.6-11%,12-14 and by routine antibiotic prophylaxis targeting GBS using a riskbased approach.13,14 In contrast to the report by Salem et al,7 we did not find antenatal steroid therapy to be associated with EOS, nor did we confirm the association between EOS and maternal age.6,7 Delivery room resuscitation and low Apgar scores have been associated with an increased risk of

FIGURE 2

Percent of VLBW infants with early onset sepsis in relation to the duration of membrane rupture and amnionitis

The effect of duration of ROM with or without amnionitis on the rate of early onset sepsis is described. ROM, rupture of membranes; VLBW, very-low-birthweight. Klinger. Epidemiology and risk factors for early onset sepsis. Am J Obstet Gynecol 2009.

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sepsis.4 Because of the close interaction between Apgar score and resuscitation, only delivery room resuscitation was included in our models. ROM of 24 hours or more was associated with a more than 2-fold increase in the odds of EOS. In nonselected newborn populations, ROM duration of above 18 hours has been associated with an increased risk of EOS.15-19 Interestingly, if ROM duration increased beyond 36 hours the rate of EOS did not increase further. Herbst and Kallen have reported a linear increase in the risk of sepsis with increasing ROM duration in full-term infants, and similarly showed no further increase in risk if ROM duration was greater than 36 hours.20 Clinical amnionitis was strongly associated with EOS confirming the report by Ronnestad et al.6 We have shown that clinical amnionitis and duration of ROM ⱖ 24 hours were both independently associated with an increased risk of EOS. ROM ⱖ 24 hours and clinical amnionitis had a cumulative effect on the risk of EOS and the presence of both factors was associated with an 8- to 10fold increase in the risk of EOS. The present study is the largest to date to study risk factors for EOS in VLBW infants. Our study population was a national cohort, exclusion criteria were minimal, and infants were followed when transferred between hospitals, avoiding selection bias. All neonatal intensive care units (NICUs) used standard definitions that have remained unchanged throughout the study period. Some limitations should, however, be considered when assessing the results of this study. The effect of antibiotic therapy on the risk of EOS could not be assessed since data on antenatal antibiotic therapy are not included in the database. Antibiotic therapy may influence the risk of EOS when PROM or amnionitis are present. However, this limitation is mitigated to some extent because according to the GBS prophylaxis guidelines that are applied in Israel,14 the majority of women would have received antibiotic therapy prior to delivery due to PROM, amnionitis, maternal fever, or imminent delivery of a preterm infant.18,19 Our study used a clinical definition of

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TABLE 3

Multivariable analyses of factors associated with early onset sepsis in very-low-birthweight infants Odds ratio (95% confidence interval)

Variable

All infants with early onset sepsis (n ⴝ 383)

Infants with early onset sepsis excluding CONS (n ⴝ 315)

Maternal age

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

20-34 y (Ref)

1.0

1.0

ⱕ 19 y

1.43 (0.77-2.64)

1.11 (0.53-2.34)

ⱖ 35 y

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

1.15 (0.90-1.48)

1.18 (0.90-1.55)

Ethnicity (non-Jewish vs Jewish)

0.78 (0.59-0.98)

0.85 (0.64-1.12)

No antenatal care vs 1st trimester care

1.94 (1.32-2.86)

2.15 (1.43-3.24)

Fertility treatment

0.98 (0.73-1.32)

1.01 (0.72-1.41)

Multiparity

0.78 (0.57-1.00)

0.78 (0.51-0.96)

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

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

Antenatal steroid therapy

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

Complete (Ref)

1.0

1.0

Partial

0.85 (0.62-1.16)

0.70 (0.54-1.11)

None

0.94 (0.73-1.21)

0.98 (0.74-1.29)

Maternal hypertensive disorders

0.90 (0.63-1.11)

0.76 (0.48-1.19)

Premature contractions

1.11 (0.87-1.40)

1.11 (0.86-1.44)

Cesarean delivery

0.88 (0.69-1.11)

0.81 (0.63-1.05)

No amnionitis ⫹ ROM ⬍ 12 h (Ref)

1.0

1.0

No amnionitis ⫹ ROM 12-24 h

1.08 (0.47-2.46)

1.26 (0.51-3.12)

No amnionitis ⫹ ROM ⱖ 24 h

2.10 (1.53-2.88)

2.40 (1.68-3.41)

Amnionitis ⫹ ROM ⬍ 24 h

4.28 (2.97-6.16)

5.58 (3.79-8.21)

Amnionitis ⫹ ROM ⱖ 24 h

8.15 (5.98-11.10)

10.91 (7.84-15.18)

Gestational age (1 wk increase)

0.98 (0.94-1.03)

0.99 (0.94-1.05)

Small for gestational age

0.84 (0.61-1.15)

0.71 (0.48-1.04)

Delivery room resuscitation

2.49 (1.91-3.24)

2.41 (1.80-3.23)

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

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

CONS, coagulase negative staphylococci; Ref, reference group; ROM, rupture of membranes. Klinger. Epidemiology and risk factors for early onset sepsis. Am J Obstet Gynecol 2009.

amnionitis. Although the strong association of sepsis with clinical amnionitis provides support to the use of clinical judgment in diagnosing amnionitis, it is possible that not all diagnoses of amnionitis were accurate. Furthermore, although Mycoplasma and Ureoplasma have recently been shown to be possible pathogens in premature infants, culture for these organisms are not routinely performed or collected.21 EOS was diagnosed if causative pathogens including CONS were isolated by blood culture and some of these cultures may represent 38.e5

contaminants. Although previous reports on EOS have considered CONS to be causative of EOS in the presence of clinical signs and symptoms compatible with sepsis,1,2 we performed 2 separate analyses with and without this pathogen that identified similar risk factors. EOS affects about 2% of VLBW infants but because of the high rates of morbidity and mortality among infants with EOS,1-3,22 a reduction in the rate of EOS would be expected to achieve a noticeable effect on survival and morbidity. Amnionitis and ROM

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ⱖ 24 hours have a strong impact on the risk of EOS; therefore, it seems prudent to treat for sepsis all VLBW infants with these risk factors until sepsis is excluded regardless of maternal antibiotic therapy. In conclusion, EOS in VLBW infants was caused mainly by gram-negative bacteria and not by GBS. Amnionitis was the strongest risk factor for EOS. ROM duration ⱖ 24 hours together with amnionitis was associated with an 8- to 10fold excess risk for EOS among VLBW infants. f REFERENCES 1. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med 2002;347:240-7. 2. Stoll BJ, Hansen NI, Higgins RD, et al. Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gramnegative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002 2003. Pediatr Infect Dis J 2005;24:635-9. 3. Stoll BJ, Gordon T, Korones SB, et al. Earlyonset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996;129:72-80. 4. Gluck L, Wood HF, Fousek MD. Septicemia of the newborn. Pediatr Clin North Am 1966;13:1131-48. 5. Klein JO. Bacterial sepsis and meningitis. In: Remington JS, Klein JO, eds. Infectious diseases of the fetus and newborn infant, 5th ed. Philadelphia: WB Saunders; 2001:943-98. 6. Ronnestad A, Abrahamsen TG, Medbo S, et al. Septicemia in the first week of life in a Norwegian national cohort of extremely premature infants. Pediatrics 2005;115:e262-8. 7. Salem SY, Sheiner E, Zmora E, Vardi H, Shoham-Vardi I, Mazor M. Risk factors for early neonatal sepsis. Arch Gynecol Obstet 2006; 274:198-202. 8. Makhoul IR, Sujov P, Smolkin T, Lusky A, Reichman B. Epidemiological, clinical, and microbiological characteristics of late-onset sepsis among very low birth weight infants in Israel: a national survey. Pediatrics 2002;109:34-9. 9. Vermont-Oxford Trials Network Database Project. Manual of operations, release 2.0, Burlington, VT; 1993. 10. Kramer MS, Platt RW, Wen S, et al. Fetal/ Infant Health Study Group of the Canadian Perinatal Surveillance System. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics. 2001; 108:E35. 11. Riskin A, Riskin-Mashiah S, Lusky A, Reichman B. The relationship between delivery mode

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www.AJOG.org and mortality in very low birthweight singleton vertex-presenting infants. BJOG 2004;111: 1365-71. 12. Schimmel MS, Eidelman AI, Rudensky B, et al. Epidemiology of group B streptococcal colonization and infection in Jerusalem, 1989-91. Isr J Med Sci 1994;30:349-51. 13. Haimov-Kochman R, Bromiker R, Milwidsky A. Prevention of perinatal group B Streptococcus disease in light of an unknown maternal carriage rate in Israel. Harefuah 2000;138: 1040-3. 14. Shrim A, Beiner M, Weisz B, Seidman DS. Perinatal group B streptococcal disease: a review and revised guidelines for prevention. Harefuah 2004;143:520-4. 15. Oddie S, Embleton ND. Risk factors for early onset neonatal group B streptococcal sepsis; case-control study. BMJ 2002;325: 308. 16. Polin RA, Parravicini E, Regan JA, Taeusch HW. Bacterial sepsis and meningitis. In: Taeusch HW, Ballard RA, Gleason CA, eds. Avery’s diseases of the newborn, 8th ed. Philadelphia: Elsevier Saunders; 2005:552-77. 17. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap L, Wenstrum KD, eds. Williams obstetrics, 22nd ed. Columbus: McGraw-HillMedicalPublishingDivision;2005: 864-80. 18. Prevention of perinatal group B streptococcal disease: a public health perspective. Cen-

ters for Disease Control and Prevention. MMWR Recomm Rep 1996;45(RR-7):1-24. 19. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep 2002;51(RR-11):1-22. 20. Herbst A, Kallen K. Time between membrane rupture and delivery and septicemia in term neonates. Obstet Gynecol 2007;110: 612-8. 21. Goldenberg RL, Andrews WW, Goepfert AR, et al. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 2008;198:43.e1-5. 22. Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network. Semin Perinatol 2003;27: 293-301.

A PPENDIX The Israel Neonatal Network, participating centers in the Israel National Very Low Birth Weight Infant Database: Coordinating center: The Women and Children’s Health Research Unit, Gertner Institute, Tel Hashomer. Neonatal departments: Assaf Harofeh Medical Center, Rishon Le Zion; Barzilay Medi-

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cal Center, Ashkelon; Bikur Holim Hospital, Jerusalem; Bnei Zion Medical Centre, Haifa; Carmel Medical Center, Haifa; English (Scottish) Hospital, Nazareth; French Hospital, Nazareth; Hadassah University Hospital Ein-Karem, Jerusalem; Hadassah University Hospital Har Hazofim, Jerusalem; Haemek Medical Center, Afula; Hillel Yafe Medical Center, Hadera; Italian Hospital, Nazareth; Kaplan Hospital, Rehovot; Laniado Hospital, Netanya; Maayanei Hayeshua Hospital, Bnei-Brak; Meir Medical Center, Kefar Saba; Misgav Ladach Hospital, Jerusalem; Naharia Hospital, Naharia; Poria Hospital, Tiberias; Rambam Medical Center, Haifa; Rivka Ziv Hospital, Zefat; Schneider Children’s Medical Center of Israel and Rabin Medical Center, Petach-Tikva; Shaare-Zedek Hospital, Jerusalem; Sheba Medical Center, Tel-Hashomer; Soroka Medical Center, Beer-Sheva; Sourasky Medical Center, Tel-Aviv; Wolfson Medical Center, Holon; Yoseftal Hospital, Eilat.

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