Hollebrandse et al are to be congratulated on achieving such a high follow-up rate at 8 years in a large cohort of preterm infants with intraventricular haemorrhage (IVH). Long-term outcomes related to specific cUS findings are increasingly important as many significant if more subtle neurodevelopmental problems are not detected at earlier follow-up.
It is reassuring that children with the milder grades of IVH had intellectual outcomes similar to the no-IVH group but of concern is the report of significant motor deficits and cerebral palsy (CP) following grades 1 and 2 IVH. However the outcomes given may not solely be related to IVH but to other pathologies notably cystic periventricular leukomalacia (cPVL) a well-known predictor of motor deficits and CP.[1,2] cPVL was found in 6% and 4% of the children with grades 1 and 2 IVH and 13% and 25% of those with grades 3 and 4 IVH. The authors neither adjust for this pathology, saying that “cPVL may lie along the causal pathway between IVH and adverse outcomes”, nor do they give evidence to support this statement. Indeed the contribution of cPVL to outcomes is not discussed or mentioned in the abstract. We are not aware of evidence that low grade IVH is in a causal pathway to cPVL, and suggested associations between cPVL and higher grades of IVH were based on studies using infrequent ultrasound protocols and without MRI scanning at term equivalent age. [3,4] We are aware of preterm infants who develop late-onset c-PVL no...
Hollebrandse et al are to be congratulated on achieving such a high follow-up rate at 8 years in a large cohort of preterm infants with intraventricular haemorrhage (IVH). Long-term outcomes related to specific cUS findings are increasingly important as many significant if more subtle neurodevelopmental problems are not detected at earlier follow-up.
It is reassuring that children with the milder grades of IVH had intellectual outcomes similar to the no-IVH group but of concern is the report of significant motor deficits and cerebral palsy (CP) following grades 1 and 2 IVH. However the outcomes given may not solely be related to IVH but to other pathologies notably cystic periventricular leukomalacia (cPVL) a well-known predictor of motor deficits and CP.[1,2] cPVL was found in 6% and 4% of the children with grades 1 and 2 IVH and 13% and 25% of those with grades 3 and 4 IVH. The authors neither adjust for this pathology, saying that “cPVL may lie along the causal pathway between IVH and adverse outcomes”, nor do they give evidence to support this statement. Indeed the contribution of cPVL to outcomes is not discussed or mentioned in the abstract. We are not aware of evidence that low grade IVH is in a causal pathway to cPVL, and suggested associations between cPVL and higher grades of IVH were based on studies using infrequent ultrasound protocols and without MRI scanning at term equivalent age. [3,4] We are aware of preterm infants who develop late-onset c-PVL not related to an initial low grade IVH but following (Gram-negative) sepsis or necrotising enterocolitis occurring later in the neonatal period.
Compared to several other studies, a high percentage of infants in this study developed CP (8% with no IVH, and 15, 18, 26 and 75% with grades 1-4 IVH). The higher levels of CP than generally expected for grades 1 and 2 IVH [5,6] may partly be explained by the presence of cPVL. Additionally there may have been non-cystic white matter injury e.g. punctate white matter lesions, cerebellar lesions or strokes that were not detected with the imaging protocol used. The statement "Our study adds to a growing understanding of the negative impact of low grade IVH on motor development" fails to adjust the findings for other lesion(s) known to lead to impaired motor development.
We also find the rates of CP in children with grades 3 and 4 IVH high. These may in part be related to care pathways chosen and the timing of treatment of post-haemorrhagic ventricular dilatation but no information is given about this.[7] One might expect about 50-60% of preterm infants with grade 4 IVH to develop a hemiplegia whilst here it is 75% perhaps influenced by the fact that 25% also had cPVL.
Another unexpected and worrying finding is that the severity of CP was the same in children with lower and higher grades of IVH. This could be due to the inclusion of infants with co-existing c-PVL or other lesions. It is unfortunate that no MRI findings are reported to substantiate the cUS findings particularly in infants with CP following low-grade IVH.
This paper may well be used by neonatologists to give prognoses following IVH in the first week after birth. We are concerned that these data will worry parents unnecessarily, especially those of infants with isolated low-grade IVH. Whilst it is fair to tell parents that other lesions may become apparent or develop we need to distinguish between outcomes due to findings seen at the time of scanning and those related to a potential pathology not yet seen and perhaps developing following unrelated clinical problems.
Yours sincerely
Frances Cowan, Floris Groenendaal and Linda S de Vries
Author affiliations:
Prof Frances M Cowan PhD FRCPCH
Dept. of Paediatrics
Hammersmith Hospital
Imperial College London
W12 0HS, UK
Email f.cowan@imperial.ac.uk
Dr Floris Groenendaal MD PhD and Prof Linda S de Vries MD PhD
Wilhelmina Children’s Hospital,
University Medical Centre Utrecht,
KE 04.123.1, PO Box 85090,
3508 AB Utrecht, Netherlands
References
1. Martinez-Biarge M, Groenendaal F, Kersbergen KJ, Benders MJNL, Foti F, van Haastert IC, Cowan FM, de Vries LS. Neurodevelopmental Outcomes in Preterm Infants with White Matter Injury Using a New MRI Classification. Neonatology. 2019;116(3):227-235
2. van Haastert IC, Groenendaal F, Uiterwaal CS, Termote JU, van der Heide-Jalving M, Eijsermans MJ, Gorter JW, Helders PJ, Jongmans MJ, de Vries LS. Decreasing incidence and severity of cerebral palsy in prematurely born children. J Pediatr. 2011 Jul;159(1):86-91.e1
3. Kusters CDJ, Chen ML, Follett PL Dammann O. "Intraventricular" hemorrhage and cystic periventricular leukomalacia in preterm infants: How are they related? J Child Neurol 2009; 24:1158-1170.
4. Kuban K, Sanocka U, Leviton A, Allred EN, Pagano M, Dammann O, et al. White matter disorders of prematurity: association with intraventricular hemorrhage and ventriculomegaly. J Pediatr 1999; 134:539-546.
5. Payne AH, Hintz SR, Hibbs AM, Walsh MC, Vohr BR, Bann CM, Wilson-Costello DE; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network: Neurodevelopmental outcomes of extremely low-gestational age neonates with low-grade periventricular intraventricular hemorrhage. JAMA Pediatr 2013;167:451–459.
6. Reubsaet P, Brouwer AJ, van Haastert IC, Brouwer MJ, Koopman C, Groenendaal F, de Vries LS. The Impact of Low-Grade Germinal Matrix-Intraventricular Hemorrhage on Neurodevelopmental Outcome of Very Preterm Infants. Neonatology 2017;112(3):203-210.
7. Leijser LM, Miller SP, van Wezel-Meijler G, Brouwer AJ, Traubici J, van Haastert IC, Whyte HE, Groenendaal F, Kulkarni AV, Han KS, Woerdeman PA, Church PT, Kelly EN, van Straaten HLM, Ly LG, de Vries LS. Posthemorrhagic ventricular dilatation in preterm infants: When best to intervene? Neurology. 2018;90(8):e698-e706
Footnotes
• Contributors: FMC, FD and LdeV contributed equally to the letter
• Funding: The authors have not declared a specific funding agency in the public, commercial or not-for-profit sectors.
• Competing interests: None declared.
• Provenance and peer review: Not commissioned.
• Patient consent for publication: Not required.
I was interested to read this study looking at a question which is extremely important to mothers of preterm infants who need to exclusively express - "how frequently do I need to express?".
The conclusion that there is no difference in average yield of mothers expressing 5, 6, 7, 8, and 9 times a day will be very useful to mothers who are similar to those included in the study - that is mothers of preterm babies aged at least 10 days (but mostly 15-20 days old), who have good daily expressed milk yield (average yield clustered around 750ml/day for these expressing frequencies). Therefore mothers in this group may feel more confident in reducing their expressing sessions down to a more manageable 5 or 6 per day, which reduces their burden of expressing.
However it could be harmful to extrapolate outside of these characteristics, for example mothers attempting to establish their supply in the first 2 weeks of life. We know that this period may be a critical window to establish milk supply and this study cannot comment on the relationship of early expressing frequency to the establishment of adequate yield (which, to complicate matters further, is poorly defined in the context of prematurity, with a range of daily volume targets from 500-900ml suggested in the literature and by the Unicef Baby Friendly Initiative). Already I have seen the article summarised as "mothers of preterm infants should express milk at least 5 times a day" on social...
I was interested to read this study looking at a question which is extremely important to mothers of preterm infants who need to exclusively express - "how frequently do I need to express?".
The conclusion that there is no difference in average yield of mothers expressing 5, 6, 7, 8, and 9 times a day will be very useful to mothers who are similar to those included in the study - that is mothers of preterm babies aged at least 10 days (but mostly 15-20 days old), who have good daily expressed milk yield (average yield clustered around 750ml/day for these expressing frequencies). Therefore mothers in this group may feel more confident in reducing their expressing sessions down to a more manageable 5 or 6 per day, which reduces their burden of expressing.
However it could be harmful to extrapolate outside of these characteristics, for example mothers attempting to establish their supply in the first 2 weeks of life. We know that this period may be a critical window to establish milk supply and this study cannot comment on the relationship of early expressing frequency to the establishment of adequate yield (which, to complicate matters further, is poorly defined in the context of prematurity, with a range of daily volume targets from 500-900ml suggested in the literature and by the Unicef Baby Friendly Initiative). Already I have seen the article summarised as "mothers of preterm infants should express milk at least 5 times a day" on social media.
Overall this is a useful addition to the literature, but it will be important to ensure that the conclusions are not over-interpreted in clinical practice
We appreciated the paper by Dubbink-Verheij et al. evaluating the incidence of thrombosis in newborns who underwent umbilical catheterization in comparison with a control group of infants without umbilical venous catheter (UVC). While the paper highlights specific issues about UVC-related thrombosis in NICU, regarding the sites, the time of onset and the outcomes of this condition, we suggest that some relevant variables have not been taken fully in account.
Some of the comorbidity rates of the patients in the study group are not consistent with data from literature and might have had a role in the unusual high rate of thrombosis and poor outcome in the study group. The reported rates of necrotizing enterocolitis (NEC; 12.5% in the study group, 10% in the total population of the study) is significantly higher compared with that of the Vermont Oxford Network (VON); VLBW infants between 2000 and 2009 based on the VON showed a NEC incidence of 4.6-6.1%. (1)
The study reported 30 thrombotic episodes in defined locations but, remarkably, the type and the diameter of catheter utilized was not stated by the Authors. Neonates, and especially preterm neonates, have an unfavorable catheter-to-vessel diameter ratio, which is a recognized risk factor for the development of catheter-related thrombosis in CVCs. In a in vitro model Nifong and McDevitt (2) quantified the impact of the catheter to vein size ratio on fluid flow unraveling the mechanism by which risk of catheter-...
We appreciated the paper by Dubbink-Verheij et al. evaluating the incidence of thrombosis in newborns who underwent umbilical catheterization in comparison with a control group of infants without umbilical venous catheter (UVC). While the paper highlights specific issues about UVC-related thrombosis in NICU, regarding the sites, the time of onset and the outcomes of this condition, we suggest that some relevant variables have not been taken fully in account.
Some of the comorbidity rates of the patients in the study group are not consistent with data from literature and might have had a role in the unusual high rate of thrombosis and poor outcome in the study group. The reported rates of necrotizing enterocolitis (NEC; 12.5% in the study group, 10% in the total population of the study) is significantly higher compared with that of the Vermont Oxford Network (VON); VLBW infants between 2000 and 2009 based on the VON showed a NEC incidence of 4.6-6.1%. (1)
The study reported 30 thrombotic episodes in defined locations but, remarkably, the type and the diameter of catheter utilized was not stated by the Authors. Neonates, and especially preterm neonates, have an unfavorable catheter-to-vessel diameter ratio, which is a recognized risk factor for the development of catheter-related thrombosis in CVCs. In a in vitro model Nifong and McDevitt (2) quantified the impact of the catheter to vein size ratio on fluid flow unraveling the mechanism by which risk of catheter-related thrombosis increases with the size of the catheter. On that basis, in 2009 Barone et al. (3) performed a systematic ultrasound evaluation of the diameter of deep veins in newborns, suggesting that the external diameter of the catheter should not exceed 1/3 of the internal diameter of the vein to reduce the risk of thrombosis. According to these evidences, we believe that catheter caliber is a relevant variable that should be reported in studies aiming to assess the risk of CVCs-related thrombosis.
(1) Jeffrey D. Horbar, et al. Mortality and Neonatal Morbidity Among Infants 501 to 1500 Grams From 2000 to 2009, Pediatrics Jun 2012; 129; 1019
(2) Nifong TP, McDevitt TJ. The effect of catheter to vein ratio on blood flow rates in a simulated model of peripherally inserted central venous catheters. Chest. 2011 Jul; 140(1): 48–53.
(3) Barone G, D’Andrea V, Vento G, Pittiruti M: A Systematic Ultrasound Evaluation of the Diameter of Deep Veins in the Newborn: Results and Implications for Clinical Practice. Neonatology 2019;115:335-340.
Prisca Da Lozzo MD. Cristina Bibalo MD. Francesca Galdo MD. Francesco Maria Risso MD. Neonatal Intensive Care Unit, Institute for Child Health IRCCS Burlo Garofolo, Trieste, Italy.
We kindly thank Da Lozzo et al. for their reaction to our paper. Indeed, many variables may be of influence on the incidence of thrombosis in our study group.
The authors are correct that the incidence of necrotizing enterocolitis in our study group (12.5%, 5/40) is higher than expected based on literature. As shown by Battersby et al. comparing NEC incidences internationally is challenging (1). The incidence of NEC in our study group does not reflect the NEC incidence of last 15 years at our department (which was 3.7% (98/2626) in infants with a gestational age <32 weeks). Possibly, the higher incidence of NEC led to a higher incidence of thrombosis in our study. However, care should be taken when interpreting our results due to the small sample size (n=40).
Da Lozzo et al. make a valuable point about the diameter of central venous catheters. Most (25/40) umbilical venous catheters (UVCs) used in our study-group were 4Fr Vygon catheters, single or double lumen, with an external diameter of 1.5 and 1.4 mm, respectively (strange enough double lumen is smaller than single lumen). In 3/40 infants 5Fr Vygon catheters (external diameter 1.7 mm) were used and in 10/40 infants 3.5Fr Vygon catheters (external diameter 1.16 mm). In 2/40 infants the size of the catheter was not registered. We found no association between the risk of thrombosis and the size of the catheter (p=0.59). However, as stated in the discussion of our paper, the sample size of our group is too...
We kindly thank Da Lozzo et al. for their reaction to our paper. Indeed, many variables may be of influence on the incidence of thrombosis in our study group.
The authors are correct that the incidence of necrotizing enterocolitis in our study group (12.5%, 5/40) is higher than expected based on literature. As shown by Battersby et al. comparing NEC incidences internationally is challenging (1). The incidence of NEC in our study group does not reflect the NEC incidence of last 15 years at our department (which was 3.7% (98/2626) in infants with a gestational age <32 weeks). Possibly, the higher incidence of NEC led to a higher incidence of thrombosis in our study. However, care should be taken when interpreting our results due to the small sample size (n=40).
Da Lozzo et al. make a valuable point about the diameter of central venous catheters. Most (25/40) umbilical venous catheters (UVCs) used in our study-group were 4Fr Vygon catheters, single or double lumen, with an external diameter of 1.5 and 1.4 mm, respectively (strange enough double lumen is smaller than single lumen). In 3/40 infants 5Fr Vygon catheters (external diameter 1.7 mm) were used and in 10/40 infants 3.5Fr Vygon catheters (external diameter 1.16 mm). In 2/40 infants the size of the catheter was not registered. We found no association between the risk of thrombosis and the size of the catheter (p=0.59). However, as stated in the discussion of our paper, the sample size of our group is too small to confirm the influence of risk factors, such as catheter size. As suggested by Barone et al. (2), the external diameter of the catheter should not exceed 1/3 of the internal diameter of the vein to reduce the risk of thrombosis. Since the most frequently used catheter in our study was a double-lumen 4Fr catheter, these catheters would preferably have to be placed in veins with an internal diameter of least 4.2 mm to reduce the risk of thrombosis. Unfortunately, Barone et al. (2) did not report diameters of veins in the umbilical venous catheter route, nor did we measurements of these diameters in our study. Eifinger et al. (3) analyzed the diameter of the umbilical vein and its further course with use of spiral-CT examinations on stillborns. They report an umbilical vein diameter increasing from 3.4 to 11 mm, a ductus venosus diameter of 2.5 mm and an umbilical recess diameter of 5 mm and conclude the umbilical vein and its extensions are wide enough to admit a 4Fr catheter. However, diameters of veins in stillborns, without flow, may not be the same as in living children.
Ultrasonography is nowadays increasingly being used in various NICUs, including our department, to evaluate the position of UVCs during and after insertion. We agree with Da Lozzo et al. that it may be beneficial to use ultrasonography before catheterization to check the internal diameter of the venous route in order to choose the most appropriate sized catheter.
(1) Battersby C, Santhalingam T, Costeloe K, Modi N. Incidence of neonatal necrotising enterocolitis in high-income countries: a systematic review. Arch Dis Child Fetal Neonatal Ed 2018;103(2):F182-F189.
(2) Barone G, D’Andrea V, Vento G, Pittiruti M: A Systematic Ultrasound Evaluation of the Diameter of Deep Veins in the Newborn: Results and Implications for Clinical Practice. Neonatology 2019;115:335-340.
(3) Eifinger F, Fuchs Z, Koerber F, Persigehl T, Scaal M. Investigation of umbilical venous vessels anatomy and diameters as a guideline for catheter placement in newborns. Clin Anat 2018;31(2):269-274.
We have read with great interest the article by Goel et al and found it very relevant. We have also been following keenly the reports from other units on successful implementation of the KP sepsis calculator in UK. Encouraged by the positive outcomes and increased use of the KP screening tool, 3 tertiary neonatal units in the NW,namely East Lancashire Hospital NHS Trust, Royal Bolton Hospital and Royal Preston Hospital decided to collect 3 months of prospective data of EONS screening and compare its recommendations against the existing practice based on CG149. All of the aforementioned units use specific CRP cut-offs to label and treat as presumed sepsis. Between the 3 units 313 babies were screened for EONS in the 3 months at a screening rate of 8.2%. Although the KP tool would have reduced screening by a significant 72.5% in average, the combined sensitivity and specificity were 50% and 82% respectively. The KP identified all true "blood-culture positive" sepsis but a large number of babies whom the KP would not have recommended screening or observation mounted high CRP responses and ended up getting treated with antibiotics. Now none of these babies were clinically unwell or grew positive blood or CSF cultures. Hence it will be interesting to see whether maternal factors like fever or pre-eclampsia resulted in this high CRP response. It also reflects the lack of accuracy of CRP and flaw in CRP based approach. It is also worth considering whether baseline di...
We have read with great interest the article by Goel et al and found it very relevant. We have also been following keenly the reports from other units on successful implementation of the KP sepsis calculator in UK. Encouraged by the positive outcomes and increased use of the KP screening tool, 3 tertiary neonatal units in the NW,namely East Lancashire Hospital NHS Trust, Royal Bolton Hospital and Royal Preston Hospital decided to collect 3 months of prospective data of EONS screening and compare its recommendations against the existing practice based on CG149. All of the aforementioned units use specific CRP cut-offs to label and treat as presumed sepsis. Between the 3 units 313 babies were screened for EONS in the 3 months at a screening rate of 8.2%. Although the KP tool would have reduced screening by a significant 72.5% in average, the combined sensitivity and specificity were 50% and 82% respectively. The KP identified all true "blood-culture positive" sepsis but a large number of babies whom the KP would not have recommended screening or observation mounted high CRP responses and ended up getting treated with antibiotics. Now none of these babies were clinically unwell or grew positive blood or CSF cultures. Hence it will be interesting to see whether maternal factors like fever or pre-eclampsia resulted in this high CRP response. It also reflects the lack of accuracy of CRP and flaw in CRP based approach. It is also worth considering whether baseline differences in maternal sepsis rates among geographical areas have an impact of the sensitivity of the calculator. It will be helpful and interesting to know whether the authors of this study and also previously reported ones (1) had similar experience with CRP and how they addressed the issue.
Reference :
1. Davidson SL, KIng R, et al. The Kaiser-Permanente early onset sepsis calculator – a tool to reduce antibiotic use in the UK? Neonatal Society summer meeting 2016.
Dear Editor
We read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early...
Dear Editor
We read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early stage the very few who develop sepsis(7, 8).
References:
1. Goel N, Shrestha S, Smith R, et al. Screening for early onset neonatal sepsis: NICE guidance-based practice versus projected application of the Kaiser Permanente sepsis risk calculator in the UK population. Arch Dis Child Fetal Neonatal Ed. 2019 Online First Jul 11. DOI: 10.1136/archdischild-2018-316777.
2. Puopolo KM, Benitz WE, Zaoutis TE. AAP Committee on Fetus and Newborn, AAP Committee on Infectious Diseases. Management of Neonates Born at ≥35 0/7 Weeks’ Gestation with Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics. 2018;142(6):e20182894
3. Mukhopadhyay S, Puopolo KM. Risk assessment in neonatal early onset sepsis. Semin Perinatol. 2012 Dec; 36(6):408-15.
4. Benitz W.E., Han M.Y., Madan A., et al: Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998; 102: E41.
5. Benitz WE. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin Perinatol. 2010;37: 421–438.
6. Neonatal infection (early onset): antibiotics for prevention and treatment. Clinical guideline [CG149]. Published August 2012.https://www.nice.org.uk/guidance/cg149/evidence/full-guideline-pdf-18817....
7. Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, et al. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr.2017 Apr 1;171(4):365-371.
8. Berardi A, Tzialla C, Travan L et al. Secondary prevention of early-onset sepsis: a less invasive Italian approach for managing neonates at risk. Ital J Pediatr. 2018; 44: 73
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
In their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestati...
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
In their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestation.[5]
Undoubtedly, neurological development is a multi-factorial process with a multitude of influencing factors. The above described clear association between neonatal sepsis and neurological sequelae from previous studies is not only contrary to the results by Baud et al.[1], but further emphasizes the significance of their findings from the PREMILOC trial. As the authors had not discussed this relevant issue in their publications,[1] we would like to point that out.
REFERENCES
1. Baud O, Trousson C, Biran V, et al. Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth. Arch Dis Child Fetal Neonatal Ed 2019;104(1):F30–5. doi: 10.1136/archdischild-2017-313756.
2. Baud O, Maury L, Lebail F, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet 2016;387(10030):1827–36. doi: 10.1016/S0140-6736(16)00202-6.
3. Alshaikh B, Yusuf K, Sauve R. Neurodevelopmental outcomes of very low birth weight infants with neonatal sepsis: systematic review and meta-analysis. J Perinatol 2013;33:558–64. doi: 10.1038/jp.2012.167.
4. Mitha A, Foix-L'Hélias L, Arnaud C, et al. Neonatal infection and 5-year neurodevelopmental outcome of very preterm infants. Pediatrics 2013;132:e372–80. doi: 10.1542/peds.2012-3979.
5. Alshaikh B, Yee W, Lodha A, et al. Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome. J Perinatol 2014;34:125–9. doi: 10.1038/jp.2013.155.
Sir,
In their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the...
Sir,
In their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the risk of drug accumulation by using novel dosing recommendations.
References
1. Favie LMA, Groenendaal F, van den Broek MPH, et al. Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia. PLoS One 2019;14(2):e0211910.
2. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987;1(8527):243-8.
3. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992;326(1):1-9.
4. May TL, Seder DB, Fraser GL, et al. Moderate-dose sedation and analgesia during targeted temperature management after cardiac arrest. Neurocrit Care 2015;22(1):105-11.
Floris Groenendaal and Richard van Lingen, 7 January 2020
Thank you for an interesting case but the position of the arterial catheter after the perforation suggests to me that this was from an umbilical artery rather than the aorta (compare the path on the abdominal wall on the 2 x-rays).
This may therefore be why you were able to successfully manage this conservatively.
Thank you for this interesting article, which really adds to our understanding of management of neonatal hypoglycaemia. However, your conclusion that a subset of babies should receive formula rather than breastfeed alongside gel, depending on their blood glucose level, is not supported by the evidence you have provided and ignores the potential harm associated with this approach.
Your data states that alongside the first use of gel, breastfed babies are more likely to require a second gel. There is no literature to support the idea that experiencing a second transient hypoglycaemia in a carefully monitored baby in the first 48 hours of life is harmful (indeed UK guidance uses a treatment threshold of 2mmol/l for the entire first 48 hours of life), and alongside the second gel breastfeeding is as effective as formula so there is no reason to suppose from the data provided that breastfed babies are more likely to go on to require intravenous dextrose.
Asking breastfeeding mothers to use formula instead of breastfeeding in the first hours of their baby's life is likely to undermine mothers' trust in breastfeeding, may impact on their milk supply through reduced stimulation in the critical time period and reduces the colostrum volume ingested, with its unique immune properties. It is not a recommendation to be made lightly.
Hollebrandse et al are to be congratulated on achieving such a high follow-up rate at 8 years in a large cohort of preterm infants with intraventricular haemorrhage (IVH). Long-term outcomes related to specific cUS findings are increasingly important as many significant if more subtle neurodevelopmental problems are not detected at earlier follow-up.
It is reassuring that children with the milder grades of IVH had intellectual outcomes similar to the no-IVH group but of concern is the report of significant motor deficits and cerebral palsy (CP) following grades 1 and 2 IVH. However the outcomes given may not solely be related to IVH but to other pathologies notably cystic periventricular leukomalacia (cPVL) a well-known predictor of motor deficits and CP.[1,2] cPVL was found in 6% and 4% of the children with grades 1 and 2 IVH and 13% and 25% of those with grades 3 and 4 IVH. The authors neither adjust for this pathology, saying that “cPVL may lie along the causal pathway between IVH and adverse outcomes”, nor do they give evidence to support this statement. Indeed the contribution of cPVL to outcomes is not discussed or mentioned in the abstract. We are not aware of evidence that low grade IVH is in a causal pathway to cPVL, and suggested associations between cPVL and higher grades of IVH were based on studies using infrequent ultrasound protocols and without MRI scanning at term equivalent age. [3,4] We are aware of preterm infants who develop late-onset c-PVL no...
Show MoreI was interested to read this study looking at a question which is extremely important to mothers of preterm infants who need to exclusively express - "how frequently do I need to express?".
The conclusion that there is no difference in average yield of mothers expressing 5, 6, 7, 8, and 9 times a day will be very useful to mothers who are similar to those included in the study - that is mothers of preterm babies aged at least 10 days (but mostly 15-20 days old), who have good daily expressed milk yield (average yield clustered around 750ml/day for these expressing frequencies). Therefore mothers in this group may feel more confident in reducing their expressing sessions down to a more manageable 5 or 6 per day, which reduces their burden of expressing.
However it could be harmful to extrapolate outside of these characteristics, for example mothers attempting to establish their supply in the first 2 weeks of life. We know that this period may be a critical window to establish milk supply and this study cannot comment on the relationship of early expressing frequency to the establishment of adequate yield (which, to complicate matters further, is poorly defined in the context of prematurity, with a range of daily volume targets from 500-900ml suggested in the literature and by the Unicef Baby Friendly Initiative). Already I have seen the article summarised as "mothers of preterm infants should express milk at least 5 times a day" on social...
Show MoreWe appreciated the paper by Dubbink-Verheij et al. evaluating the incidence of thrombosis in newborns who underwent umbilical catheterization in comparison with a control group of infants without umbilical venous catheter (UVC). While the paper highlights specific issues about UVC-related thrombosis in NICU, regarding the sites, the time of onset and the outcomes of this condition, we suggest that some relevant variables have not been taken fully in account.
Show MoreSome of the comorbidity rates of the patients in the study group are not consistent with data from literature and might have had a role in the unusual high rate of thrombosis and poor outcome in the study group. The reported rates of necrotizing enterocolitis (NEC; 12.5% in the study group, 10% in the total population of the study) is significantly higher compared with that of the Vermont Oxford Network (VON); VLBW infants between 2000 and 2009 based on the VON showed a NEC incidence of 4.6-6.1%. (1)
The study reported 30 thrombotic episodes in defined locations but, remarkably, the type and the diameter of catheter utilized was not stated by the Authors. Neonates, and especially preterm neonates, have an unfavorable catheter-to-vessel diameter ratio, which is a recognized risk factor for the development of catheter-related thrombosis in CVCs. In a in vitro model Nifong and McDevitt (2) quantified the impact of the catheter to vein size ratio on fluid flow unraveling the mechanism by which risk of catheter-...
We kindly thank Da Lozzo et al. for their reaction to our paper. Indeed, many variables may be of influence on the incidence of thrombosis in our study group.
Show MoreThe authors are correct that the incidence of necrotizing enterocolitis in our study group (12.5%, 5/40) is higher than expected based on literature. As shown by Battersby et al. comparing NEC incidences internationally is challenging (1). The incidence of NEC in our study group does not reflect the NEC incidence of last 15 years at our department (which was 3.7% (98/2626) in infants with a gestational age <32 weeks). Possibly, the higher incidence of NEC led to a higher incidence of thrombosis in our study. However, care should be taken when interpreting our results due to the small sample size (n=40).
Da Lozzo et al. make a valuable point about the diameter of central venous catheters. Most (25/40) umbilical venous catheters (UVCs) used in our study-group were 4Fr Vygon catheters, single or double lumen, with an external diameter of 1.5 and 1.4 mm, respectively (strange enough double lumen is smaller than single lumen). In 3/40 infants 5Fr Vygon catheters (external diameter 1.7 mm) were used and in 10/40 infants 3.5Fr Vygon catheters (external diameter 1.16 mm). In 2/40 infants the size of the catheter was not registered. We found no association between the risk of thrombosis and the size of the catheter (p=0.59). However, as stated in the discussion of our paper, the sample size of our group is too...
We have read with great interest the article by Goel et al and found it very relevant. We have also been following keenly the reports from other units on successful implementation of the KP sepsis calculator in UK. Encouraged by the positive outcomes and increased use of the KP screening tool, 3 tertiary neonatal units in the NW,namely East Lancashire Hospital NHS Trust, Royal Bolton Hospital and Royal Preston Hospital decided to collect 3 months of prospective data of EONS screening and compare its recommendations against the existing practice based on CG149. All of the aforementioned units use specific CRP cut-offs to label and treat as presumed sepsis. Between the 3 units 313 babies were screened for EONS in the 3 months at a screening rate of 8.2%. Although the KP tool would have reduced screening by a significant 72.5% in average, the combined sensitivity and specificity were 50% and 82% respectively. The KP identified all true "blood-culture positive" sepsis but a large number of babies whom the KP would not have recommended screening or observation mounted high CRP responses and ended up getting treated with antibiotics. Now none of these babies were clinically unwell or grew positive blood or CSF cultures. Hence it will be interesting to see whether maternal factors like fever or pre-eclampsia resulted in this high CRP response. It also reflects the lack of accuracy of CRP and flaw in CRP based approach. It is also worth considering whether baseline di...
Show MoreDear Editor
Show MoreWe read with interest the letter by Sur et al in response to our article (1). It was very reassuring to note that our findings were replicated in their study confirming the potential scale of antibiotic reduction while identifying all ‘blood culture positive’ sepsis. We did not collect data on CRP in our study. The evidence does not support a single CRP measurement as a reliable tool to help decisions to initiate treatment in the context of early onset neonatal sepsis (EOS), particularly in asymptomatic infants[2]. Consistent normal values over first 48 hours are associated with absence of EOS; but abnormal values in an asymptomatic infant are unreliable to predict culture proven sepsis [2-5]. CRP concentrations increase in neonates in response to a number of non-infective inflammatory conditions such as asphyxia, meconium aspiration, tissue trauma and pneumothorax. Serial CRP trend is irrelevant in treatment initiation decisions, and in low incidence conditions such as EOS, its value in predicting true culture positive EOS is below that is expected of a good and reliable test (Likelihood ratio 3.0)[4,6). The American Academy of Paediatrics states that diagnosis of EOS cannot be made using CRP in the absence of positive blood or CSF culture [2]. For asymptomatic low / moderate risk infants (currently treated with presumptive antibiotics), a period of observation / serial physical examination may be used instead of invasive tests to identify at an early...
In their follow-up analysis of the PREMILOC trial, Baud et al.[1] found significantly better neurodevelopmental outcomes at 22 months postmenstrual age in those extreme preterm neonates of 24 and 25 weeks of gestation who had been treated with early hydrocortisone during the first ten days after birth. Improvements in global neurological assessments were most pronounced for moderate to severe neurodevelopmental impairment, with a prevalence of 2.1% in the hydrocortisone and 18.4% in the placebo group. In this context it has to be remembered that early hydrocortisone treatment had been associated with a significant increase in the late-onset sepsis rate before discharge for those most immature neonates of 24 and 25 weeks of gestation.[2]
Show MoreIn their meta-analysis including seventeen observational studies, Alshaikh et al.[3] described “an increased risk of one or more long-term neurodevelopmental impairments … including cerebral palsy” in very-low-birth-weight infants who had suffered from culture-proven sepsis during the neonatal period. A follow-up analysis of extreme preterm neonates below 32 weeks of gestation found a significantly higher frequency of cerebral palsy at five years of age in those who had developed early- and/or late-onset sepsis.[4] Correspondingly, a positive association of Coagulase-negative staphylococcus sepsis and the risk of cognitive delay at a corrected age between 30 and 42 months has been reported in preterm neonates below 29 weeks of gestati...
Sir,
Show MoreIn their paper Montaldo et al. suggest that routine use of morphine in infants with perinatal asphyxia and therapeutic hypothermia (TH) is not useful and potentially harmful (Arch Dis Child Fetal Neonatal Ed. 2020:108-09). They rightfully suggest that morphine may accumulate during TH. However, in a recent study using multicentre data we have proposed novel dosing schedules for morphine and midazolam during TH thereby avoiding the risk of drug accumulation1.
Montaldo et al. state that “… it is unclear if morphine suppresses the nociceptive cortical activity in babies…” referring to a study of oral morphine for acute procedural pain in preterm infants.
Only since the late 1980s opioids are used during neonatal surgery following two classical papers by Anand showing that pre-emptive opioid analgesia following cardiac surgery in human infants dramatically decreased mortality and morbidity rates by suppressing pain and stress2 3.
As written by Montaldo et al. the right of universal pain relief is undisputed, also in human infants, and it is generally accepted through many animal experiments that TH is stressful. Furthermore, sedation and analgesia during TH after cardiac arrest in adults is well tolerated and effective4.
Therefore we are very reluctant to remove the mandatory use of sedatives including morphine from our international Dutch and Flemish guideline of TH, and we would like to stimulate others to use analgesia, while avoiding the...
Thank you for an interesting case but the position of the arterial catheter after the perforation suggests to me that this was from an umbilical artery rather than the aorta (compare the path on the abdominal wall on the 2 x-rays).
This may therefore be why you were able to successfully manage this conservatively.
Thank you for this interesting article, which really adds to our understanding of management of neonatal hypoglycaemia. However, your conclusion that a subset of babies should receive formula rather than breastfeed alongside gel, depending on their blood glucose level, is not supported by the evidence you have provided and ignores the potential harm associated with this approach.
Your data states that alongside the first use of gel, breastfed babies are more likely to require a second gel. There is no literature to support the idea that experiencing a second transient hypoglycaemia in a carefully monitored baby in the first 48 hours of life is harmful (indeed UK guidance uses a treatment threshold of 2mmol/l for the entire first 48 hours of life), and alongside the second gel breastfeeding is as effective as formula so there is no reason to suppose from the data provided that breastfed babies are more likely to go on to require intravenous dextrose.
Asking breastfeeding mothers to use formula instead of breastfeeding in the first hours of their baby's life is likely to undermine mothers' trust in breastfeeding, may impact on their milk supply through reduced stimulation in the critical time period and reduces the colostrum volume ingested, with its unique immune properties. It is not a recommendation to be made lightly.
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