Stillbirths are tragic events with devastating consequences on women and couples: all efforts to better understand, manage and prevent their occurrence are welcome. Nevertheless, we have some concerns on what reported by De Curtis et al, who suggested an increase of stillbirth rate during the COVID-19 pandemic lockdown in Lazio, Italy.
1. First, we do not believe that a crude comparison with the corresponding months of 2019 is a proper control. Stillbirths are rare events, with a variable incidence during the year and alternating phases of low incidence and clusters of cases. The assumption that in the period Mar-May 2020 their number in the Lazio region should have been the same as of Mar-May 2019 is unsubstantiated. Consistently, the incidence reported by the authors in Lazio for 2020 (3.23 ‰) is almost the same of what reported for the same region in 2019 yearly statistics (3.00 ‰) [1] in which stillbirth is defined as a loss after 180 days (25 wks + 5 days). Furthermore, when using the 22 wks definition, reported stillbirth rate for Italy is significantly higher (4.70 ‰) [2].
2. Second, the authors suggest that the supposed increase could be due to reduced visits to hospitals due to the fear of contracting COVID-19. Unfortunately, this claim (that indeed blames women for the loss of their unborn child) is not at all supported by facts, as it wasn’t in the manuscript that the authors cite as a reference. Data from a sample of 2448 women who were pregnant or...
Stillbirths are tragic events with devastating consequences on women and couples: all efforts to better understand, manage and prevent their occurrence are welcome. Nevertheless, we have some concerns on what reported by De Curtis et al, who suggested an increase of stillbirth rate during the COVID-19 pandemic lockdown in Lazio, Italy.
1. First, we do not believe that a crude comparison with the corresponding months of 2019 is a proper control. Stillbirths are rare events, with a variable incidence during the year and alternating phases of low incidence and clusters of cases. The assumption that in the period Mar-May 2020 their number in the Lazio region should have been the same as of Mar-May 2019 is unsubstantiated. Consistently, the incidence reported by the authors in Lazio for 2020 (3.23 ‰) is almost the same of what reported for the same region in 2019 yearly statistics (3.00 ‰) [1] in which stillbirth is defined as a loss after 180 days (25 wks + 5 days). Furthermore, when using the 22 wks definition, reported stillbirth rate for Italy is significantly higher (4.70 ‰) [2].
2. Second, the authors suggest that the supposed increase could be due to reduced visits to hospitals due to the fear of contracting COVID-19. Unfortunately, this claim (that indeed blames women for the loss of their unborn child) is not at all supported by facts, as it wasn’t in the manuscript that the authors cite as a reference. Data from a sample of 2448 women who were pregnant or gave birth during COVID-19 lockdown in Italy [3] show indeed the opposite: concern for their own health was quite low in Italian mothers, while wellbeing of their child and care of their pregnancy were considered the most important tasks during lockdown [4].
3. Ravaldi C, Vannacci A, The COVID-ASSESS dataset - COVID19 related anxiety and stress in prEgnancy, poSt-partum and breaStfeeding during lockdown in Italy. Data in Brief 2020 33, 106440 https://doi.org/10.1016/j.dib.2020.106440
4. Ravaldi C, Wilson A, Ricca V, Homer C, Vannacci A, Pregnant women voice their concerns and birth expectations during the COVID-19 pandemic in Italy, Women Birth (2020), doi: 10.1016/j.wombi.2020.07.002
We thank Drs Cowan, de Vries and Groenendaal for their interest in our study.(1) Their main concerns related to our findings that low-grade intraventricular haemorrhages (IVH) were associated with higher rates of cerebral palsy than experienced in their own centres and other published studies, and that other lesions apart from low-grade IVH may explain the higher rates of motor impairment and cerebral palsy noted in our cohorts.
Our cerebral palsy rates were determined at age 8 years, by experienced developmental paediatricians blinded to group and clinical history. Thus we are confident of the robustness of clinical ascertainment. We accept that our reported rates of cerebral palsy in low-grade IVH may be higher than those in some other studies, highlighting that our findings are likely specific to our population rather than others. However, our finding of increased cerebral palsy in low-grade IVH is not isolated, as we identified several studies describing 1.5-2 times the baseline rates in preterm cohorts born <33 weeks’ with low-grade IVH compared with no IVH.(2-4) We acknowledge that our data supports an association between low-grade IVH and cerebral palsy, and at no point did we imply a causal relationship.
We agree that cystic periventricular leukomalacia (cPVL) is a well-established cause of cerebral palsy. Co-existing cPVL in our low-grade IVH groups did not explain the associations with cerebral palsy. The independent relationships between low-gra...
We thank Drs Cowan, de Vries and Groenendaal for their interest in our study.(1) Their main concerns related to our findings that low-grade intraventricular haemorrhages (IVH) were associated with higher rates of cerebral palsy than experienced in their own centres and other published studies, and that other lesions apart from low-grade IVH may explain the higher rates of motor impairment and cerebral palsy noted in our cohorts.
Our cerebral palsy rates were determined at age 8 years, by experienced developmental paediatricians blinded to group and clinical history. Thus we are confident of the robustness of clinical ascertainment. We accept that our reported rates of cerebral palsy in low-grade IVH may be higher than those in some other studies, highlighting that our findings are likely specific to our population rather than others. However, our finding of increased cerebral palsy in low-grade IVH is not isolated, as we identified several studies describing 1.5-2 times the baseline rates in preterm cohorts born <33 weeks’ with low-grade IVH compared with no IVH.(2-4) We acknowledge that our data supports an association between low-grade IVH and cerebral palsy, and at no point did we imply a causal relationship.
We agree that cystic periventricular leukomalacia (cPVL) is a well-established cause of cerebral palsy. Co-existing cPVL in our low-grade IVH groups did not explain the associations with cerebral palsy. The independent relationships between low-grade IVH and cerebral palsy at 8 years remained after adjusting for cPVL [unadjusted OR 2.24 (95% confidence interval (CI) 1.21, 4.16); p=0.011; adjusted for cPVL OR 2.22 (95% CI 1.14, 4.29) p=0.018]. As brain magnetic resonance imaging was not widely available for the cohorts in this study, we are not able to confirm the possibility of other lesions explaining the rates of cerebral palsy observed in our low-grade IVH groups.
Our paper highlights the associations of all grades of IVH with adverse outcomes at school age. Regardless of whether the associations are explained by other brain lesions, the findings highlight the importance of long term follow up in all extremely preterm newborns in regard to risk of neurodevelopmental deficits, including those with low-grade IVH.
Jeanie Cheong, Alicia Spittle, Peter Anderson and Lex Doyle
References:
1) Hollebrandse NL, Spittle AJ, Burnett AC, et al. School-age outcomes following intraventricular haemorrhage in infants born extremely preterm. Arch Dis Child Fetal Neonatal Ed 2020 Jul 30:fetalneonatal-2020-318989. doi: 10.1136/archdischild-2020-318989.
2) Klebermass-Schrehof K, Czaba C, Olischar M, et al. Impact of low-grade intraventricular hemorrhage on long-term neurodevelopmental outcome in preterm infants. Childs Nerv Syst 2012;28:2085–92.
3) Bolisetty S, Dhawan A, Abdel-Latif M, et al. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics 2014;133:55–62.
4) Beaino G, Khoshnood B, Kaminski M, et al. Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. Dev Med Child Neurol 2010;52:e119–25.
Dr O’Shea and colleagues provide useful trainee perspective on the use of videolaryngoscopy as a teaching aid and highlight the need for standardised training packages.
We performed a qualitative study using semi-structured interviews of 22 consultants and trainees in a UK tertiary neonatal unit where videolaryngoscopy is commonly used. Interviews were recorded and transcribed verbatim. Data was analysed using attribute and descriptive coding methods. Framework Analysis was used to interpret the data obtained from interviews.
In our study, videolaryngoscopy was felt to have largely positive effects on facilitating safer training in an era where intubation opportunities are lacking. As with O’Shea et al,(1) our participants felt that videolaryngoscopy allowed considerably easier demonstration of intubation techniques. Interviewees commented that looking at the monitor combined with the movements of the operator and coaching in real-time, assisted eye-hand co-ordination and made it easier to correct technique. Visual feedback would benefit kinaesthetic learning as per the VARK: Visual, Aural, Read/write, and Kinesthetic learning styles, although the existence of these styles is debated.(2,3)
In our study, interviewees felt that use of videolaryngosopy allowed group teaching, and instilled confidence in those watching in what was occurring. This ‘team learning’ aligns with social cognitive theory, where learning experiences are active and social, with re...
Dr O’Shea and colleagues provide useful trainee perspective on the use of videolaryngoscopy as a teaching aid and highlight the need for standardised training packages.
We performed a qualitative study using semi-structured interviews of 22 consultants and trainees in a UK tertiary neonatal unit where videolaryngoscopy is commonly used. Interviews were recorded and transcribed verbatim. Data was analysed using attribute and descriptive coding methods. Framework Analysis was used to interpret the data obtained from interviews.
In our study, videolaryngoscopy was felt to have largely positive effects on facilitating safer training in an era where intubation opportunities are lacking. As with O’Shea et al,(1) our participants felt that videolaryngoscopy allowed considerably easier demonstration of intubation techniques. Interviewees commented that looking at the monitor combined with the movements of the operator and coaching in real-time, assisted eye-hand co-ordination and made it easier to correct technique. Visual feedback would benefit kinaesthetic learning as per the VARK: Visual, Aural, Read/write, and Kinesthetic learning styles, although the existence of these styles is debated.(2,3)
In our study, interviewees felt that use of videolaryngosopy allowed group teaching, and instilled confidence in those watching in what was occurring. This ‘team learning’ aligns with social cognitive theory, where learning experiences are active and social, with regular interaction of colleagues in a real-life setting.(4) This social interaction and kinaesthetic activity results in reflection, thus building on their previous knowledge of intubation as per situated learning theory.(5)
Videolaryngoscopy was felt to reduce anxiety levels, improving patient safety whilst learning. Some participants expressed concerns that gaining proficiency in videolaryngoscopy might place the trainee at a disadvantage at another hospital where videolaryngoscopes were not in common use. Videolaryngoscopy is a useful adjunct for intubation training but cannot completely replace direct laryngoscopy due to some differences in technique, equipment and the lack of availability across centres.
References
1 O’ Shea JE, Kirolos S, Thio M, et al. Neonatal videolaryngoscopy as a teaching aid: the trainees’ perspective. Arch Dis Child FetalNeonatal Ed. Published Online First: 22 September 2020. doi: 10.1136/archdischild-2020-319619.
2 Fleming ND, Mills C. Not another inventory, rather a catalyst for reflection. To Improve the Academy 1992;11,137-155.
3 Husmann PR, O’Loughlin VD. Another Nail in the Coffin for Learning Styles? Disparities among Undergraduate Anatomy Students' Study Strategies, Class Performance, and Reported VARK Learning Styles.Anat Sci Educ 2020;(12)1:6-19.
4 Wenger E. Communities of Practice. Learning, meaning and identity. Cambridge: Cambridge University Press 2000.
5 Lave J, Wenger E. Situated learning: Legitimate peripheral participation. Cambridge: Cambridge University Press 1991.
Hedermann and colleagues reported a decreased rate of extremely premature birth as a potential beneficial effect of nationwide COVID-19 lockdown in Denmark1. Although this study provides important new evidence that enhances our understanding of the aetiology of extreme prematurity, comparisons with other populations are vital for delineating the mechanisms underlying the observed beneficial effect. Moreover, uncertainty remains about the direct and indirect impacts of the COVID-19 pandemic and its associated lockdowns on live births globally. To begin to address these gaps in knowledge, we used preliminary administrative data from the Brazilian Live Births Information System (SINASC) to assess the effect of COVID-19 and its associated disruptions on prematurity rates in a middle-income country with a high incidence of SARS-CoV-2 infections. Similarly, to Hedermann and colleagues1, we included the months of most intensive social distance interventions (17th March to 31st May 2020)2 and excluded registrations with multiple births. However, to adapt for the Brazilian data, we also excluded congenital abnormalities and used as comparison the same period but only for the year of 2019, due to the Zika virus epidemic that occurred in previous years. We included 613,640 live births from 2019 and 560,691 from 2020. Overall, we observed similar rates of premature births in both years; the proportion of extremely preterm births was 4.57/1000 live births in 2019 vs 4.52/1000 live bi...
Hedermann and colleagues reported a decreased rate of extremely premature birth as a potential beneficial effect of nationwide COVID-19 lockdown in Denmark1. Although this study provides important new evidence that enhances our understanding of the aetiology of extreme prematurity, comparisons with other populations are vital for delineating the mechanisms underlying the observed beneficial effect. Moreover, uncertainty remains about the direct and indirect impacts of the COVID-19 pandemic and its associated lockdowns on live births globally. To begin to address these gaps in knowledge, we used preliminary administrative data from the Brazilian Live Births Information System (SINASC) to assess the effect of COVID-19 and its associated disruptions on prematurity rates in a middle-income country with a high incidence of SARS-CoV-2 infections. Similarly, to Hedermann and colleagues1, we included the months of most intensive social distance interventions (17th March to 31st May 2020)2 and excluded registrations with multiple births. However, to adapt for the Brazilian data, we also excluded congenital abnormalities and used as comparison the same period but only for the year of 2019, due to the Zika virus epidemic that occurred in previous years. We included 613,640 live births from 2019 and 560,691 from 2020. Overall, we observed similar rates of premature births in both years; the proportion of extremely preterm births was 4.57/1000 live births in 2019 vs 4.52/1000 live births in 2020, and very premature births were 8.52/1000 live births in 2019 vs 8.89/1000 live births in 2020. Unlike the reports from Denmark, these preliminary data suggest that Brazil has not experienced a reduction in the prevalence of extremely premature birth during the early months of the COVID-19 pandemic and its associated interventions. It has been hypothesized that the association between the lockdowns and preterm birth rates may be attributed to underlying mechanisms, such as reduced pregnancy-associated stress, increased support systems, altered work practices, governmental financial assistance, and decreased incidence of infections during pregnancy3. In Brazil, it is plausible that the limited and heterogeneously implemented social distance measures and high incidence of SARS-CoV-2 combined with the pre-existing social inequities, substantial background burden of other infectious diseases, and current crises may have compromised the beneficial impact observed in Denmark1. Alternatively, the results observed in Denmark could be a spurious association due to small numbers or an increased number of pregnancies ending in intrauterine death, as highlighted by the authors1. We welcome the presentation of data from Hedermann and colleagues1, but the contrasting results from Brazil highlight the need for international comparisons to better interpret the impact of COVID-19 public health policies4.
CPAP is the standard method of respiratory support in preterm neonates. BCPAP is the most widely used type of CPAP in low- and middle-income countries due to its simplicity of design, ease of use and low cost.[1] Efficacy of BCPAP has been compared against other pressure generating devices in many small RCTs and is the topic of interest amongst neonatologists. Latest systematic review involving 12 eligible studies including 1194 subjects shows a significant reduction of CPAP failure in BCPAP group [RR 0.75 ,95% CI (0.57-0.98)] without any significant impact on mortality, BPD and air leak.[2] However, we want to identify few issues with the review which if addressed, may shift the pooled treatment effect towards ‘null’.
First, authors have used the random-effects meta-analysis (REM) to calculate the pooled effect size. A fixed-effects meta-analysis assumes that all individual studies are trying to estimate a single true effect of the intervention and the pooled estimate is the ‘typical’ intervention effect.[3] However, the REM assumes that different studies are estimating different (but related) treatment effect which have a distribution (assumed to be a normal distribution). The pooled estimate obtained with REM is hence an ‘average’ intervention effect based on the assumption that intervention effects seen in all the individual studies are available for pooling. Therefore, before conducting a REM, publication bias needs to be excluded. If a publication bias exists,...
CPAP is the standard method of respiratory support in preterm neonates. BCPAP is the most widely used type of CPAP in low- and middle-income countries due to its simplicity of design, ease of use and low cost.[1] Efficacy of BCPAP has been compared against other pressure generating devices in many small RCTs and is the topic of interest amongst neonatologists. Latest systematic review involving 12 eligible studies including 1194 subjects shows a significant reduction of CPAP failure in BCPAP group [RR 0.75 ,95% CI (0.57-0.98)] without any significant impact on mortality, BPD and air leak.[2] However, we want to identify few issues with the review which if addressed, may shift the pooled treatment effect towards ‘null’.
First, authors have used the random-effects meta-analysis (REM) to calculate the pooled effect size. A fixed-effects meta-analysis assumes that all individual studies are trying to estimate a single true effect of the intervention and the pooled estimate is the ‘typical’ intervention effect.[3] However, the REM assumes that different studies are estimating different (but related) treatment effect which have a distribution (assumed to be a normal distribution). The pooled estimate obtained with REM is hence an ‘average’ intervention effect based on the assumption that intervention effects seen in all the individual studies are available for pooling. Therefore, before conducting a REM, publication bias needs to be excluded. If a publication bias exists, some studies in the distribution of treatment effects are missing and REM should not be done. This systematic review includes more than 10 studies, the conventionally accepted threshold for assessing the publication bias. Yet, this important step is missed. Given small size of ‘positive’ studies favoring BCPAP, one cannot exclude absence of ‘negative’ unpublished studies.
Second, authors define time-point for the ‘CPAP failure’ at 7 days of use. No consensus exists on what time-point constitutes the ideal cut-off for defining the failure and many studies report 72 h (or other time-points) as the cutoff. We are not sure whether authors were able to obtain the 7-day failure data from all the included studies. In our assessment of the studies, we were able to retrieve the 7-day outcome in only 4 of 12 studies.
Third, it is not clear which risk of bias assessment (ROB) tool has been used by the authors. While the text mentions the use of ROB-2 tool,[4] the risk of bias figures uses the original Cochrane ROB framework.[3]As criteria of the assessment of risk of bias are different in these tools, same domain in a study can be classified to be at high- or low-risk of bias with these two ROB tools. Use of both the tools in a single review may confuse the readers.
Fourth, nasal injury, one of the review outcomes is reported to be twice [RR 2.04(95% CI 1.33-3.14)] more common with BCPAP. The authors have attributed the higher risk of nasal injury to oscillatory effect of BCPAP. But we tend to disagree with this as there is neither sufficient evidence nor biological rationale behind this plausibility. Rather the incidence of nasal injury is highly dependent on the type of nasal interface used.[5] Different CPAP devices use different types of nasal interfaces and individual trials may not have ensured the use of identical interface.
Finally, authors have used meta-regression to investigate the effect of co-variates on the success of CPAP device. However, the choice of co-variates used in the meta-regression (country of origin, type of CPAP used in control arm and risk of bias) seems to be driven by availability bias. Type of nasal interface, starting CPAP pressure, actual measurement and matching of airway pressure in the BCPAP arm of the trial are more important and unaddressed confounding factors.
Contributors SK(supreetkhurana85@gmail.com) and DC contributed to all steps of making this letter.
Funding None.
Competing interest None Declared.
Patient Consent for publication Not required.
References
1. Thukral A, Sankar MJ, Chandrasekaran A, et al. Efficacy and safety of CPAP in low- and middle-income countries. J Perinatol 2016;36(1):S21-S28.
2. Bharadwaj SK, Alonazi A, Banfield L, et al. Bubble versus other continuous positive airway pressure forms: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal 2020;105:526-531.
3. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.1 [updated September 2020].The Cochrane Collaboration, 2020. Available from training.cochrane.org/handbook/current.(accessed 20 Sep 2020)
4. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.
5. Imbulana DI, Manley BJ, Dawson JA, et al. Nasal injury in preterm infants receiving non-invasive respiratory support: a systematic review. Arch Dis Child Fetal Neonatal Ed 2018 Jan;103(1):F29-F35.
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.
CMV exposure of breast milk fed infants from seropositive mothers is a well known phenomenon. Patel et al. excellent research has shed a very important and troubling consequence of this infection on very low birth premature babies. Yet, some of the information needed for decision making and recommendations is lacking from the published data. From the data we see that 17% (76 of 457 infants) of seropositive mothers decided not to give there babies any breast milk in contrast to 0% ! of seronegative mothers. I think that in order to make a proper decision we need to compare the incidence of Necrotizing Enterocolitis and other complications of prematurity between this group of exclusively formula fed babies and CMV infected babies. Although the numbers may not be sufficient for statistical analysis we might benefit as caregivers from this important information.
Dear Editor,
We read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that...
Dear Editor,
We read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that found insufficient evidence supporting the routine use of therapeutic hypothermia in NE. According to our results, we need high quality and stronger RCTs to improve the knowledge on an important topic.
References
1. Kariholu U, Montaldo P, Markati T, et al. Therapeutic hypothermia for mild neonatal encephalopathy: a systematic review and meta-analysis. Archives of Disease in Childhood - Fetal and Neonatal Edition 2020;105:225-228
2. Ridgeon EE, Young PJ, Bellomo R, et al. The Fragility Index in multicenter randomized controlled critical care trials. Crit Care Med 2016;44:1278–1284
3. Vargas M, Servillo G. The End of Corticosteroid in Sepsis: Fragile Results From Fragile Trials. Crit Care Med 2018 46:e1228
4. Vargas M, Servillo G. Liberal versus conservative oxygen therapy in critically ill patients: using the fragility index to determine robust results. Crit Care 2019;23:132
5. Vargas M, Buononanno P, Marra A et al. Fragility Index in Multicenter Randomized Controlled Trials in Critical Care Medicine That Have Shown Reduced Mortality. Crit Care Med. 2020;48:e250-e251
All of these extubation-readyness tests assess respiratory drive / lungs. However, it may be for many preterms that they struggle to maintain their airway despite good drive and lungs that are relatively healthy. This aspect can't be tested and could explain why so many infants who seem able to breath don't do so once the ETT has been taken out.
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3),...
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3), and speculated that this was due to lack of sedation. On the other hand, Gunn et al. demonstrated significant improvement in neuropathology scores in fetal lambs cooled for 72 hours without sedation compared with those that were not(4).
Secondary analysis from the National Institute of Child Health and Human Development (NICHD) (5)and Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE) (6)studies examined the effect of sedation in term infants during therapeutic hypothermia. Routine sedation was not associated with neuroprotection, but increased the hospital stay.
There are many difficulties in quantifying pain in neonates undergoing therapeutic hypothermia. Often shivering is equated to stress, which may only indicate depletion of brown fat(7). Clinicians tend to use sedation to stop shivering, although the evidence to support this practice is unclear(8). We are only suggesting that the jury is still out on pre-emptive opioid sedation during therapeutic hypothermia, and at present, it is unclear whether this practice beneficial or harmful. This issue can be answered only by developing better markers for quantifying stress in infants with encephalopathy and rigorously evaluating the safety and efficacy of opioid therapy during therapeutic hypothermia in clinical trials.
References
1. Anand KJ, Hall RW, Desai N, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet (London, England) 2004; 363(9422): 1673-82.
2. Montaldo P, Vakharia A, Ivain P, et al. Pre-emptive opioid sedation during therapeutic hypothermia. Archives of disease in childhood Fetal and neonatal edition 2020; 105(1): 108-9.
3. Thoresen M, Satas S, Loberg EM, et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatric research 2001; 50(3): 405-11.
4. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. The Journal of clinical investigation 1997; 99(2): 248-56.
5. Natarajan G, Shankaran S, Laptook AR, et al. Association between sedation-analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy. Journal of perinatology : official journal of the California Perinatal Association 2018; 38(8): 1060-7.
6. Liow N, Montaldo P, Lally PJ, et al. Preemptive Morphine During Therapeutic Hypothermia After Neonatal Encephalopathy: A Secondary Analysis. Therapeutic hypothermia and temperature management 2019.
7. Hu HH, Wu TW, Yin L, et al. MRI detection of brown adipose tissue with low fat content in newborns with hypothermia. Magnetic resonance imaging 2014; 32(2): 107-17.
8. Pitoni S, Sinclair HL, Andrews PJ. Aspects of thermoregulation physiology. Current opinion in critical care 2011; 17(2): 115-21.
Stillbirths are tragic events with devastating consequences on women and couples: all efforts to better understand, manage and prevent their occurrence are welcome. Nevertheless, we have some concerns on what reported by De Curtis et al, who suggested an increase of stillbirth rate during the COVID-19 pandemic lockdown in Lazio, Italy.
Show More1. First, we do not believe that a crude comparison with the corresponding months of 2019 is a proper control. Stillbirths are rare events, with a variable incidence during the year and alternating phases of low incidence and clusters of cases. The assumption that in the period Mar-May 2020 their number in the Lazio region should have been the same as of Mar-May 2019 is unsubstantiated. Consistently, the incidence reported by the authors in Lazio for 2020 (3.23 ‰) is almost the same of what reported for the same region in 2019 yearly statistics (3.00 ‰) [1] in which stillbirth is defined as a loss after 180 days (25 wks + 5 days). Furthermore, when using the 22 wks definition, reported stillbirth rate for Italy is significantly higher (4.70 ‰) [2].
2. Second, the authors suggest that the supposed increase could be due to reduced visits to hospitals due to the fear of contracting COVID-19. Unfortunately, this claim (that indeed blames women for the loss of their unborn child) is not at all supported by facts, as it wasn’t in the manuscript that the authors cite as a reference. Data from a sample of 2448 women who were pregnant or...
We thank Drs Cowan, de Vries and Groenendaal for their interest in our study.(1) Their main concerns related to our findings that low-grade intraventricular haemorrhages (IVH) were associated with higher rates of cerebral palsy than experienced in their own centres and other published studies, and that other lesions apart from low-grade IVH may explain the higher rates of motor impairment and cerebral palsy noted in our cohorts.
Our cerebral palsy rates were determined at age 8 years, by experienced developmental paediatricians blinded to group and clinical history. Thus we are confident of the robustness of clinical ascertainment. We accept that our reported rates of cerebral palsy in low-grade IVH may be higher than those in some other studies, highlighting that our findings are likely specific to our population rather than others. However, our finding of increased cerebral palsy in low-grade IVH is not isolated, as we identified several studies describing 1.5-2 times the baseline rates in preterm cohorts born <33 weeks’ with low-grade IVH compared with no IVH.(2-4) We acknowledge that our data supports an association between low-grade IVH and cerebral palsy, and at no point did we imply a causal relationship.
We agree that cystic periventricular leukomalacia (cPVL) is a well-established cause of cerebral palsy. Co-existing cPVL in our low-grade IVH groups did not explain the associations with cerebral palsy. The independent relationships between low-gra...
Show MoreDr O’Shea and colleagues provide useful trainee perspective on the use of videolaryngoscopy as a teaching aid and highlight the need for standardised training packages.
We performed a qualitative study using semi-structured interviews of 22 consultants and trainees in a UK tertiary neonatal unit where videolaryngoscopy is commonly used. Interviews were recorded and transcribed verbatim. Data was analysed using attribute and descriptive coding methods. Framework Analysis was used to interpret the data obtained from interviews.
In our study, videolaryngoscopy was felt to have largely positive effects on facilitating safer training in an era where intubation opportunities are lacking. As with O’Shea et al,(1) our participants felt that videolaryngoscopy allowed considerably easier demonstration of intubation techniques. Interviewees commented that looking at the monitor combined with the movements of the operator and coaching in real-time, assisted eye-hand co-ordination and made it easier to correct technique. Visual feedback would benefit kinaesthetic learning as per the VARK: Visual, Aural, Read/write, and Kinesthetic learning styles, although the existence of these styles is debated.(2,3)
Show MoreIn our study, interviewees felt that use of videolaryngosopy allowed group teaching, and instilled confidence in those watching in what was occurring. This ‘team learning’ aligns with social cognitive theory, where learning experiences are active and social, with re...
Hedermann and colleagues reported a decreased rate of extremely premature birth as a potential beneficial effect of nationwide COVID-19 lockdown in Denmark1. Although this study provides important new evidence that enhances our understanding of the aetiology of extreme prematurity, comparisons with other populations are vital for delineating the mechanisms underlying the observed beneficial effect. Moreover, uncertainty remains about the direct and indirect impacts of the COVID-19 pandemic and its associated lockdowns on live births globally. To begin to address these gaps in knowledge, we used preliminary administrative data from the Brazilian Live Births Information System (SINASC) to assess the effect of COVID-19 and its associated disruptions on prematurity rates in a middle-income country with a high incidence of SARS-CoV-2 infections. Similarly, to Hedermann and colleagues1, we included the months of most intensive social distance interventions (17th March to 31st May 2020)2 and excluded registrations with multiple births. However, to adapt for the Brazilian data, we also excluded congenital abnormalities and used as comparison the same period but only for the year of 2019, due to the Zika virus epidemic that occurred in previous years. We included 613,640 live births from 2019 and 560,691 from 2020. Overall, we observed similar rates of premature births in both years; the proportion of extremely preterm births was 4.57/1000 live births in 2019 vs 4.52/1000 live bi...
Show MoreCPAP is the standard method of respiratory support in preterm neonates. BCPAP is the most widely used type of CPAP in low- and middle-income countries due to its simplicity of design, ease of use and low cost.[1] Efficacy of BCPAP has been compared against other pressure generating devices in many small RCTs and is the topic of interest amongst neonatologists. Latest systematic review involving 12 eligible studies including 1194 subjects shows a significant reduction of CPAP failure in BCPAP group [RR 0.75 ,95% CI (0.57-0.98)] without any significant impact on mortality, BPD and air leak.[2] However, we want to identify few issues with the review which if addressed, may shift the pooled treatment effect towards ‘null’.
Show MoreFirst, authors have used the random-effects meta-analysis (REM) to calculate the pooled effect size. A fixed-effects meta-analysis assumes that all individual studies are trying to estimate a single true effect of the intervention and the pooled estimate is the ‘typical’ intervention effect.[3] However, the REM assumes that different studies are estimating different (but related) treatment effect which have a distribution (assumed to be a normal distribution). The pooled estimate obtained with REM is hence an ‘average’ intervention effect based on the assumption that intervention effects seen in all the individual studies are available for pooling. Therefore, before conducting a REM, publication bias needs to be excluded. If a publication bias exists,...
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 MoreCMV exposure of breast milk fed infants from seropositive mothers is a well known phenomenon. Patel et al. excellent research has shed a very important and troubling consequence of this infection on very low birth premature babies. Yet, some of the information needed for decision making and recommendations is lacking from the published data. From the data we see that 17% (76 of 457 infants) of seropositive mothers decided not to give there babies any breast milk in contrast to 0% ! of seronegative mothers. I think that in order to make a proper decision we need to compare the incidence of Necrotizing Enterocolitis and other complications of prematurity between this group of exclusively formula fed babies and CMV infected babies. Although the numbers may not be sufficient for statistical analysis we might benefit as caregivers from this important information.
Dear Editor,
Show MoreWe read with great interest the systematic review and meta-analysis by Kariholu et al on the evaluation of therapeutic hypothermia as a tool to decrease composite outcome like death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE). [1]. The authors, including 5 randomized controlled trials (RCTs) reporting the considered outcome, found insufficient evidence to recommend routine therapeutic hypothermia for NE [1]. We agree with this statement and we’d like to support it evaluating the fragility index of the RCTs included in this meta-analysis.
The fragility index (FI), an intuitive measure of the robustness of RCTs, was introduced in critical care medicine [2]. The studies with larger FI have more robust findings compared with the studies with poor FI [2]. Recently the FI was applied to different meta-analyses in order to confirm or not the results by including in the analysis the studies with FI greater than zero [3, 4, 5]. We evaluated the FI of the RCTs included in this meta-analysis using a two-by-two contingency table and p-value produced by Fisher exact test [2]. In line with the high risk of bias of the included RCTs, we found no studies with FI more than zero for death or moderate/severe disability (Battin FI=0 p= 0,455, Gluckman FI=0 p=1, Jacobs FI=0 p= 0,729, Thayyil FI=0 p=0.350, Zhou FI=0 p=1) [1].
Since all the included studies are fragile, we strongly support the author’s conclusion that...
All of these extubation-readyness tests assess respiratory drive / lungs. However, it may be for many preterms that they struggle to maintain their airway despite good drive and lungs that are relatively healthy. This aspect can't be tested and could explain why so many infants who seem able to breath don't do so once the ETT has been taken out.
We thank Floris Gronendal et al. for their views on our sedation survey and highlighting their personal opinion about mandatory sedation during therapeutic hypothermia. They quote two seminal preliminary studies on preterm infants by Anand recruiting 16 and 30 babies each, but not the later definitive Neopain trial on 898 babies, that showed increased adverse outcome (death, intraventricular bleed, periventricular leukomalacia) with morphine, to support their views(1).
Our survey was intended to examine the current practice of pre-emptive opioid sedation during therapeutic hypothermia in ventilated and non-ventilated infants (2). We have only highlighted the variation of sedation practices during therapeutic hypothermia and potentially toxic morphine doses used by some neonatal units in the UK and we have not made any recommendation about using or not routine sedation during therapeutic hypothermia. Such recommendations can only be based on scientific evidence, not on surveys or personal views, and this unfortunately is lacking. Clearly hypothermia in children and adults do require heavy sedation, but we do not feel that these data can be directly extrapolated to newborn infants.
Preclinical studies on sedation during therapeutic hypothermia are conflicting. Thoresen et al. showed no reduction in neuropathology scores in a piglet model for hypoxic injury without general anaesthesia that were cooled for 24 hours compared with those that were not cooled(3),...
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