OBJECTIVE. To determine the impact of intrauterine inflammation of maternal (chorioamnionitis) and fetal (umbilical vasculitis) origin and neonatal sepsis on the development of neonatal chronic lung disease in preterm infants.
METHODS. This study was conducted at Royal Prince Alfred Hospital in Sydney, Australia. All infants born at <30 weeks' gestation, admitted to the NICU, and surviving to 36 weeks' corrected gestation during 1992–2004 were eligible. Infants with major congenital abnormalities and those without placental examination were excluded. Antenatal and perinatal data extracted from hospital databases were correlated with the independent, central neonatal database and diagnostic laboratory reports. Neonatal sepsis was categorized according to blood culture isolates into 3 groups: coagulase-negative staphylococci, other bacteria, and Candida species.
RESULTS. There were 798 eligible infants born during the study period, and 761 (95.4%) had placental examination. The mean gestational age was 27.4 ± 1.5 weeks. Antenatal maternal steroids were given to 94.4%. Regression analysis showed that chorioamnionitis with umbilical vasculitis and increasing gestation were associated with reduced odds of chronic lung disease. Chorioamnionitis without umbilical vasculitis showed a trend to reduced odds of chronic lung disease. Birth weight at <3rd percentile and neonatal sepsis were associated with increased odds of chronic lung disease.
CONCLUSIONS. A fetal inflammatory response is protective for chronic lung disease. Neonatal sepsis is strongly associated with chronic lung disease, and the infecting organism is important. Coagulase-negative staphylococcal infection confers a risk for chronic lung disease similar to that of other bacteremias. Candidemia confers the greatest risk of chronic lung disease.
Infections with coagulase-negative staphylococci and chronic lung disease in very-low-birth-weight infants
Christoph Härtel, Egbert Herting and Wolfgang Göpel for the German Neonatal Network (GNN)University of Lübeck, Department of Pediatrics, Ratzeburger Allee 160, 23538 Lübeck, Germany
Dear Editor,
With great interest we read the article by Lahra and colleagues on the relationship between sepsis with coagulase-negative staphylococci (CoNS) and the development of chronic lung disease (CLD) in preterm infants (1). Given the fact that CoNS are often interpreted as microorganisms with less clinical significance, the authors’ findings are remarkable and are supported by the data from our recently founded German Neonatal Network (GNN). From October 2003 until April 2008, 14 tertiary care centers in Germany prospectively enrolled 2327 very-low-birth-weight (VLBW) infants (gestational age: 28.8 ± 2.7 weeks, birth weight: 1075 ± 294 g, mean ± SD). 190/2327 (8.2%) VLBW infants developed blood-culture proven CoNS sepsis, 236/2327 (10.1%) infants had sepsis from other organisms, and 21/2327 (0.9%) infants suffered from Candida sepsis. In our cohort, 69/2327 (3.0%) infants died, CLD (oxygen demand at 36 weeks postmenstrual age) was diagnosed in 306/2327 (13.1%) infants, while 132/2327 (5.6%) infants required supplemental oxygen when discharged. VLBW infants with CoNS sepsis were found to have an increased risk for CLD compared to those without CoNS sepsis (31.1 % vs. 11.6%, p<0.001). In a stepwise logistic regression model, gestational age (per week), birth weight at < 10th percentile, and neonatal sepsis (reference: no blood- culture proven sepsis; CoNS sepsis; sepsis from other bacteria than CoNS; candida sepsis) were selected for analysis (table 1). CoNS sepsis was proven to be an independent risk factor for both, CLD and the combined outcome parameter CLD/death. Effective prevention strategies against CoNS infections may therefore have a significant impact on the incidence of CLD in the highly susceptible population of VLBW infants.
Reference 1 Lahra MM, Beeby PJ, Jeffery HE. Intrauterine Inflammation, Neonatal Sepsis, and Chronic Lung Disease: A 13-year Hospital Cohort Study. Pediatrics 2009; 123: 1314-1319.
Conflict of Interest:
None declared
Authors response:
We are grateful to Drs. Tornese, Tonetti, and Marchetti for this thoughtful letter noting the lack of evidence to support the recommendation of a trial of human chorionic gonadotropin (hCG) for cryptorchidism in Prader-Willi syndrome (PWS). Unfortunately, space limitations in the article made it impossible to fully discuss the reasoning and evidence behind every recommendation. The Health Supervision Guidelines are based on four pillars of clinical decision making -- available experimentally derived evidence, clinical experience, reason, and tradition. In this instance, the writers point to an area in which the recommendation was based primarily on the experience and reason of multiple physicians who have provided care to individuals with PWS.
Lacking direct evidence in males with PWS as to the best approach, we have taken a conservative approach, based on the following principles. First, cryptorchidism is extremely common in PWS. Although the field of pediatric anesthesia has made tremendous progress in developing safe approaches to children with special needs, common sense dictates that the most effective risk-reduction method is to avoid the need for anesthesia in the first place. In a few cases, especially when the testis is palpable in the distal inguinal canal, surgery may be avoided with use of hormonal therapy.
The writers refer to the “unfavorable balance between benefit and dangers” of hCG therapy, referencing a publication describing a short-term increase in germ cell apoptosis in the testes of boys treated with hCG compared with the rate before therapy(1), hypothesizing that this could possibly lead to reduced fertility. Fertility has not been reported in males with PWS; therefore, preservation of fertility is not a major issue in these boys, and a rapid move to surgery is less compelling. The same argument may be made for the potential to reduce risk of later testicular tumors by early surgical intervention, as this complication has not been described in a boy with PWS, to our knowledge. That does not mean that it cannot happen, merely that the risk may be less in males with PWS than in typically developing males. Further, the statement from the AAP Section on Urology(2) does not discuss use of hormonal therapy at all but, rather, summarizes the evidence at that time (1996) regarding the ideal timing of surgery to maximize future fertility.
The hypogonadism associated with PWS points to several other potentially salutary affects of hCG. First, the phallus is often small, which can interfere with standing micturition. Treatment with hCG can lead to significant improvement of this problem. Second, although the hCG therapy may not move the testis into the scrotum, there is often some progress in descent related to therapy, thus making the surgery easier and more likely to be successful. Likewise, the underdeveloped scrotum may also grow in response to the hormonal therapy, again increasing the ease and potential success of the definitive surgical repair.
We appreciate the opportunity to further amplify the reasoning behind the recommendation. Clearly, this question deserves a well-designed clinical study, and we thank the correspondents for highlighting the need for evidence-based therapy.
Shawn E. McCandless, MD, FAAP, FACMG for the Committee on Genetics
References:
1) Heiskanen P, Billig H, Toppari J, Kaleva M, Arsalo A, Rapola J, Dunkel L. Apoptotic cell death in the normal and cryptorchid human testis: the effect of human chorionic gonadotropin on testicular cell survival. Pediatr Res. 1996;40(2):351-6.
2) American Academy of Pediatrics, Section on Urology. Timing of elective surgery on the genitalia of male children with particular reference to the risks, benefits, and psychological effects of surgery and anesthesia. Pediatrics. 1996;97(4):590–594.
Conflict of Interest:
None declared
Dear Editor,
With great interest we read the article by Lahra and colleagues on the relationship between histological chorioamnionitis, neonatal sepsis and chronic lung disease in preterm infants [1]. Their findings underline the complexity of the associations between antenatal inflammation and adverse lung development [2].
Contrary to what the authors convey, we believe it would be quite informative to include mechanical ventilation in the multivariable model investigating the association between chorioamnionitis and CLD. In fact, the authors hypothesised that ‘intrauterine inflammation would decrease CLD as a consequence of reduced RDS and associated ventilation’. Although their findings may be suggestive of such a mechanism, comparing the models with and without addition of either RDS or mechanical ventilation could actually test this hypothesis. Would a reduction in mechanical ventilation have caused the negative association between chorioamnionitis and CLD, adjustment for this variable should diminish or even obliterate the association. In addition, adjustment for mechanical ventilation is crucial to rule out the possibility that the association between sepsis and CLD is merely the result of increased mechanical ventilation in infants with sepsis. Furthermore, inclusion of two-way interaction terms for the variables of interest may reveal informative subgroup-specific associations, as elegantly shown by Van Marter and colleagues [3].
We would be much interested to learn the effects of addition of mechanical ventilation / RDS to the model on the associations between chorioamnionitis, sepsis, and development of CLD.
1. Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics 2009;123(5):1314-19.
2. Been JV, Zimmermann LJ. Histological chorioamnionitis and respiratory outcome in preterm infants. Arch Dis Child Fetal Neonatal Ed 2009;94(3):F218-25.
3. Van Marter LJ, Dammann O, Allred EN, Leviton A, Pagano M, Moore M, Martin C. Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002;140(2):171-6.
Conflict of Interest:
None declared