We thank the authors for the comments on the Economic Evaluation of SIFT (1) and we are grateful for the opportunity to respond to their comments.
Taking each of the authors’ points in the order in which they are presented:
1. In relation to the first point about the loss to follow up and the exclusion of such patients from the analysis, we point out that we used complete case analysis and accounted for the missing patients following best practice using a multiple imputation analysis which is provided in the supplementary materials. We state the following in the paper:
“Mean total costs for all infants, adjusting for missing data using multiple imputation, are found in the online supplementary table S3. When the missing values were accounted for, faster feed increments remain more costly in comparison to slower feed increments but at a slightly higher level (£378 more) per infant, reflecting the high level of uncertainty in the difference in costs, especially with regard to the healthcare resource use after discharge estimated by the multiple imputation” (last paragraph of methods))
2. In relation to the authors second concern, whilst death was slightly higher in the slower feeds arm during initial hospital stay there are two important points in response to this. First, we clarify that by definition economic analysis is not an exercise in accountancy where death is assumed to incur a zero cost, because economic evaluation focuses on costs and ou...
We thank the authors for the comments on the Economic Evaluation of SIFT (1) and we are grateful for the opportunity to respond to their comments.
Taking each of the authors’ points in the order in which they are presented:
1. In relation to the first point about the loss to follow up and the exclusion of such patients from the analysis, we point out that we used complete case analysis and accounted for the missing patients following best practice using a multiple imputation analysis which is provided in the supplementary materials. We state the following in the paper:
“Mean total costs for all infants, adjusting for missing data using multiple imputation, are found in the online supplementary table S3. When the missing values were accounted for, faster feed increments remain more costly in comparison to slower feed increments but at a slightly higher level (£378 more) per infant, reflecting the high level of uncertainty in the difference in costs, especially with regard to the healthcare resource use after discharge estimated by the multiple imputation” (last paragraph of methods))
2. In relation to the authors second concern, whilst death was slightly higher in the slower feeds arm during initial hospital stay there are two important points in response to this. First, we clarify that by definition economic analysis is not an exercise in accountancy where death is assumed to incur a zero cost, because economic evaluation focuses on costs and outcomes together in a ratio. Thus, death causes a severe penalty in the denominator of the analysis as fewer survivors in the denominator means the cost effectiveness is less favorable ( eg. Dividing an integer by a zero gives a result tending to infinity). Second, death alone was not the primary outcome. The primary outcome was neurodevelopmental disability at aged 2, since surviving with severe disability will incur substantial cost.
3. With respect to point 3, we refer to the response to point one - in accordance with best practice multiple imputation was carried out to account for missing data.
4. We do not exclude the parental nutrition costs - these are presented in the first line of Table 1 and are supported by the reference of Walter et al. (see reference 28) in the paper (1)
5. In terms of generalizability, whilst the transferability of healthcare resource use and costs will be affected by differences in clinical practice and relative prices across countries, varying costs alone may not be sufficient (2).
Finally, whilst our paper concluded that SIFT would not be deemed cost- effective, that result was not driven by the costs alone. The clinical paper showed no statistical difference in the primary outcome of survival without moderate or severe disability (3). The recommended approach to economic evaluation is not to use statistical significance but to estimate and quantify the uncertainty that is implied using simulation techniques. Following these techniques the analysis suggested that the Sift intervention of faster feeds had potential to be harmful as reported in the paper. To assume that the results of the paper are driven by cost is to misunderstand health economics and the definition of cost-effectiveness which is not based on cost alone but a ratio of the difference in costs divided by the difference in effects.
Yours sincerely
Tracy Roberts On behalf of all co authors
Sift authorship
References:
1. Tahir W, Monahan M, Dorling J, et al. Economic evaluation alongside the Speed of Increasing milk Feeds Trial (SIFT). Arch Dis Child Fetal Neonatal Ed. 2020 Nov;105(6):587-592. doi: 10.1136/archdischild-2019-318346.
2. Drummond M, Barbieri M, Cook J, Glick HA, Lis J, Malik F, et al. Transferability of economic evaluations across jurisdictions: ISPOR Good Research Practices Task Force report. Value in health. 2009; 12 (4):409–18. https://doi.org/10.1111/j.1524-4733.2008.00489.x PMID: 19900249).
3. Dorling J, Abbott J, Berrington J, et al; SIFT Investigators Group. Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants. N Engl J Med. 2019 Oct 10;381(15):1434-1443. doi: 10.1056/NEJMoa1816654.
I read with interest the economic evaluation of Speed of Increasing milk Feeds Trial (SIFT) in preterm infants presented by Tahir and colleagues.(1) While the clinical findings from the SIFT had shown short-term benefits such as lesser TPN days with faster feed increments, and was equivocal for the composite primary outcome of death and disability measured at 24 months, this analysis recommends against faster feed increments based on the cost-effectiveness analyses. The average total costs is shown to be marginally higher for subjects in this arm, with a mean difference of £267 (0.25%). I highlight below many issues that probably affect the conclusions, and the generalizability of the findings, of this economic evaluation.
First, the trial enrolled 1394 and 1399 patients in the two study arms. However, the cost data of initial hospitalization is presented for 1224 and 1246 patients in these arms. It seems that 170 and 153 patients from the two trial arms were lost to follow-up after the initial hospitalization;(2) however, the data for these subjects should not be excluded while calculating the average initial hospitalization costs per subject.
Second, more deaths during the initial hospitalization were reported in the slower increment arm and those probably lowered the average cost for this arm. It is well known that the hospitalization costs for very preterm infants that die during the neonatal period are substantially lower than those of the survivors....
I read with interest the economic evaluation of Speed of Increasing milk Feeds Trial (SIFT) in preterm infants presented by Tahir and colleagues.(1) While the clinical findings from the SIFT had shown short-term benefits such as lesser TPN days with faster feed increments, and was equivocal for the composite primary outcome of death and disability measured at 24 months, this analysis recommends against faster feed increments based on the cost-effectiveness analyses. The average total costs is shown to be marginally higher for subjects in this arm, with a mean difference of £267 (0.25%). I highlight below many issues that probably affect the conclusions, and the generalizability of the findings, of this economic evaluation.
First, the trial enrolled 1394 and 1399 patients in the two study arms. However, the cost data of initial hospitalization is presented for 1224 and 1246 patients in these arms. It seems that 170 and 153 patients from the two trial arms were lost to follow-up after the initial hospitalization;(2) however, the data for these subjects should not be excluded while calculating the average initial hospitalization costs per subject.
Second, more deaths during the initial hospitalization were reported in the slower increment arm and those probably lowered the average cost for this arm. It is well known that the hospitalization costs for very preterm infants that die during the neonatal period are substantially lower than those of the survivors.(3)
Third, health services costs for 2 years after the initial hospitalization was collected via a patient questionnaire, completed by 842 and 873 parents for the two trial arms. The missing data on a large percentage of study subjects could have resulted in biased estimates for these costs.
Fourth, unit cost of resource items presented in table 1, omit the parenteral nutrition costs that tend to be substantial.(4) Since the trial showed less parenteral nutrition use in the faster arm, the inclusion of these costs (as planned in the protocol), could have had a significant impact on the analyses.
Also, this economic evaluation lacks generalizability, in terms of its applicability to other jurisdictions, as no sensitivity analyses were conducted for a range of cost values for salient resource items that vary significantly across countries with similar economic development. For example, the costs listed for community paediatrician’s visit (£407 per visit) and donor breast milk (£335/litre) are 4 to 6 times higher than the typical costs for these items in the North America.
References
1. Tahir W, Monahan M, Dorling J, et al. Economic evaluation alongside the Speed of Increasing milk Feeds Trial (SIFT). Arch Dis Child Fetal Neonatal Ed. 2020 Nov;105(6):587-592. doi: 10.1136/archdischild-2019-318346.
2. Dorling J, Abbott J, Berrington J, et al; SIFT Investigators Group. Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants. N Engl J Med. 2019 Oct 10;381(15):1434-1443. doi: 10.1056/NEJMoa1816654.
3. Phibbs CS, Schmitt SK, Cooper M, et al. Birth Hospitalization Costs and Days of Care for Mothers and Neonates in California, 2009-2011. J Pediatr. 2019 Jan;204:118-125.e14. doi: 10.1016/j.jpeds.2018.08.041.
4. Walter E, Liu FX, Maton P, et al. Cost analysis of neonatal and pediatric parenteral nutrition in Europe: a multi-country study. Eur J Clin Nutr. 2012 May;66(5):639-44. doi: 10.1038/ejcn.2011.225.
“Parenteral nutrition for preterm infants: Correcting for arachidonic and
docosahexaenoic acid may not suffice” by Bernard et al. regarding the publication:
Frazer LC, Martin CR. Parenteral lipid emulsions in the preterm infant: current issues
and controversies. Arch Dis Child Fetal Neonatal Ed. 2021 Jan 29: fetalneonatal-
2020-319108. doi: 10.1136/archdischild-2020-319108. Epub ahead of print. PMID:
33514630.
Lauren C. Frazer1,2, Camilia R. Martin2,3,4
1Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA
2Department of Pediatrics, Harvard Medical School, Boston, MA, USA
3Division of Translational Research, Beth Israel Deaconess Medical Center, Boston, MA, USA 4Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, MA, USA
Correspondence: cmartin1@bidmc.harvard.edu
We would like to thank Bernhard and colleagues for their thoughtful letter “Parenteral nutrition for preterm infants: Correcting for arachidonic and docosahexaenoic acid may not suffice” written in response to our review. The authors of the letter raised important issues regarding the lack of data surrounding the optimal balance of arachidonic (ARA) and docosahexaenoic acid (DHA) that should be administered...
“Parenteral nutrition for preterm infants: Correcting for arachidonic and
docosahexaenoic acid may not suffice” by Bernard et al. regarding the publication:
Frazer LC, Martin CR. Parenteral lipid emulsions in the preterm infant: current issues
and controversies. Arch Dis Child Fetal Neonatal Ed. 2021 Jan 29: fetalneonatal-
2020-319108. doi: 10.1136/archdischild-2020-319108. Epub ahead of print. PMID:
33514630.
Lauren C. Frazer1,2, Camilia R. Martin2,3,4
1Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA
2Department of Pediatrics, Harvard Medical School, Boston, MA, USA
3Division of Translational Research, Beth Israel Deaconess Medical Center, Boston, MA, USA 4Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, MA, USA
Correspondence: cmartin1@bidmc.harvard.edu
We would like to thank Bernhard and colleagues for their thoughtful letter “Parenteral nutrition for preterm infants: Correcting for arachidonic and docosahexaenoic acid may not suffice” written in response to our review. The authors of the letter raised important issues regarding the lack of data surrounding the optimal balance of arachidonic (ARA) and docosahexaenoic acid (DHA) that should be administered to preterm neonates by these emulsions as well as the inadequacy of current lipid emulsions in providing other components such as myristic acid and choline. While we focused on long chain polyunsaturated fatty acids in our review, we agree that lipid emulsions are a complex matrix of components beyond ARA and DHA and highlighted this in Table 3 under Formulation when discussing current research gaps. We chose to highlight the fatty acid balance in this concise review because, in our experience, this topic largely drives the motivation in selecting lipid emulsions by providers in the neonatal intensive care unit. Advanced analytical methods from detection to data analysis are now available to take a comprehensive approach in understanding the metabolic influence of complex lipid emulsions in neonatal development and disease risk. Such studies are a necessary step in developing nutritional products designed to meet the unique needs of preterm infants encompassing those highlighted by Bernhard and colleagues.
Thank you,
Lauren C. Frazer, MD PhD
Camilia R. Martin, MD MS
In response to: "Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia".
We read with great interest the article by Dr Woods et al (1) that adds evidence to recent, large multicenter studies on lung ultrasound (LUS) as a predictive tool for bronchopulmonary dysplasia (BPD) (2-4). These studies, performed on a total of more than 600 infants, stem from a validated scoring system whose signs represent a progressive decrease in lung aeration in standardized ultrasound views (5). Notably, this approach is also well established in adult critical care (6).
The grading system adopted by Dr Woods and coworkers, has not been validated and its highest scores do not correspond to less air in the lung and therefore to a more severe pulmonary disease. Also, rather than the conventional sum of scores, Dr Woods et al. calculate a two-decimals mean score that may undermine the technique discrimination. None of these choices have ever been made for any other LUS scores, neither in neonates nor in older patients, despite ultrasound semiology and statistics needed to evaluate the predictive power are always the same (6). These factors may undermine the LUS prediction power for BPD.
Moreover, the authors needed a full ROC procedure to perform a formal diagnostic accuracy analysis, but even then, its strength would have been questionable with only 7 out 96 infants suffering from moderate-to-severe BPD (7) as target condition. This smal...
In response to: "Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia".
We read with great interest the article by Dr Woods et al (1) that adds evidence to recent, large multicenter studies on lung ultrasound (LUS) as a predictive tool for bronchopulmonary dysplasia (BPD) (2-4). These studies, performed on a total of more than 600 infants, stem from a validated scoring system whose signs represent a progressive decrease in lung aeration in standardized ultrasound views (5). Notably, this approach is also well established in adult critical care (6).
The grading system adopted by Dr Woods and coworkers, has not been validated and its highest scores do not correspond to less air in the lung and therefore to a more severe pulmonary disease. Also, rather than the conventional sum of scores, Dr Woods et al. calculate a two-decimals mean score that may undermine the technique discrimination. None of these choices have ever been made for any other LUS scores, neither in neonates nor in older patients, despite ultrasound semiology and statistics needed to evaluate the predictive power are always the same (6). These factors may undermine the LUS prediction power for BPD.
Moreover, the authors needed a full ROC procedure to perform a formal diagnostic accuracy analysis, but even then, its strength would have been questionable with only 7 out 96 infants suffering from moderate-to-severe BPD (7) as target condition. This small number of patients with the target disease reduces the diagnostic accuracy of any exam performed for an early prediction.
Finally, we agree with Dr Woods and colleagues that LUS is not a silver bullet, but adequate methodology should be followed to investigate it. According to data produced with this methodology LUS has a significant power for BPD prediction.
REFERENCES
1. Woods PL, Stoecklin B, Woods A, Gill AW. Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed. 2021 May 14;fetalneonatal-2020-320830.
2. Raimondi F, Migliaro F, Corsini I, Meneghin F, Dolce P, Pierri L, et al. Lung Ultrasound Score Progress in Neonatal Respiratory Distress Syndrome. Pediatrics. 2021 Apr;147(4):e2020030528.
3. Alonso-Ojembarrena A, Serna-Guerediaga I, Aldecoa-Bilbao V, Gregorio-Hernández R, Alonso-Quintela P, Concheiro-Guisán A, et al. The Predictive Value of Lung Ultrasound Scores in Developing Bronchopulmonary Dysplasia. Chest. 2021 Mar;S0012369221004682.
4. Loi B, Vigo G, Baraldi E, Raimondi F, Carnielli VP, Mosca F, et al. Lung Ultrasound to Monitor Extremely Preterm Infants and Predict BPD: Multicenter Longitudinal Cohort Study. Am J Respir Crit Care Med. 2020 Dec 22;rccm.202008-3131OC.
5. Brat R, Yousef N, Klifa R, Reynaud S, Shankar Aguilera S, De Luca D. Lung Ultrasonography Score to Evaluate Oxygenation and Surfactant Need in Neonates Treated With Continuous Positive Airway Pressure. JAMA Pediatr. 2015 Aug;169(8):e151797. doi: 10.1001/jamapediatrics.2015.1797.
6. Mongodi S, De Luca D, Colombo A, Stella A, Santangelo E, Corradi F, Gargani L, Rovida S, Volpicelli G, Bouhemad B, Mojoli F. Quantitative Lung Ultrasound: Technical Aspects and Clinical Applications. Anesthesiology. 2021 Jun 1;134(6):949-965. doi: 10.1097/ALN.0000000000003757.
7. Higgins RD, Jobe AH, Koso-Thomas M, Bancalari E, Viscardi RM, Hartert TV, et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. The Journal of Pediatrics. 2018 Jun;197:300–8.
Thanks for this excellent focus on visual abilities of infants following HIE.
More than three decades ago, at a time when brain imaging of newborns with HIE was limited to ultrasound and CT scanning, we have published impairments of visual functions at an early age (Early Hum Dev 1989;20:267-279 and Neuropediatrics 1990;21:76-78) .
We could do so using standardized, outpatient methods of visual assessment.
Further use of this relatively simple tools could and should be part of assessments of infants with HIE, in particular when (diffusion weighted) MRI indicates involvement of visual tracts.
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
De Curtis et al reported some changes occurring in perinatal outcomes during lockdown in Lazio region, Italy. In particular, according to their data, preterm deliveries were reduced while stillbirth (SB) rate seems to be three-fold increased respect with the same period of 2019 (1).
We collected the same outcomes in Emilia-Romagna (ER), a northern Italian region with 4.47 million residents. Gestational age at delivery has been obtained by Birth Certificates (CedAP) while SB occurrence was collected from the Surveillance system of SB. This system is active since 2014. It records and audits, in a multidisciplinary way, each single case reported by every birth center of the Region. SB was defined according to WHO as published elsewhere together with other details of the Audit process (2).
In Emilia-Romagna, in the quarter March to May 2020, the one of the national lockdown, there were 22 SB (≥22+0 weeks) out of 6800 singletons births, for a rate of 3.24/1000. For the same quarter, in the previous 6 years, SB rate ranged from 2.86 (22/7687) in 2016 to 4.32 (31/7170) in 2019. According to one-way analysis of variance for 2014-2020 years, SB rate not changed significantly (p value >0.05 for each years of observation).
It has to be highlighted that a small number of events allow to a great variations in the rates, in a phenomenon such as SB that has a very low prevalence. For this reason, a comparison of only two points as previously done (1) could lead artif...
De Curtis et al reported some changes occurring in perinatal outcomes during lockdown in Lazio region, Italy. In particular, according to their data, preterm deliveries were reduced while stillbirth (SB) rate seems to be three-fold increased respect with the same period of 2019 (1).
We collected the same outcomes in Emilia-Romagna (ER), a northern Italian region with 4.47 million residents. Gestational age at delivery has been obtained by Birth Certificates (CedAP) while SB occurrence was collected from the Surveillance system of SB. This system is active since 2014. It records and audits, in a multidisciplinary way, each single case reported by every birth center of the Region. SB was defined according to WHO as published elsewhere together with other details of the Audit process (2).
In Emilia-Romagna, in the quarter March to May 2020, the one of the national lockdown, there were 22 SB (≥22+0 weeks) out of 6800 singletons births, for a rate of 3.24/1000. For the same quarter, in the previous 6 years, SB rate ranged from 2.86 (22/7687) in 2016 to 4.32 (31/7170) in 2019. According to one-way analysis of variance for 2014-2020 years, SB rate not changed significantly (p value >0.05 for each years of observation).
It has to be highlighted that a small number of events allow to a great variations in the rates, in a phenomenon such as SB that has a very low prevalence. For this reason, a comparison of only two points as previously done (1) could lead artifacts.
Moreover, another source of variation is represented by the Italian law which still defines any product of conception prior to 180 days of development (25 weeks and 5 days) as a miscarriage. We already reported that this underestimate SB rate when data collection is performed by using official statistical flow respect with a prospective recording in an active surveillance program (2).
Furthermore, the proportion of very premature births (<31+6 week) and moderate/late premature births (32+0-36+6) was not significantly different between the 2020 national lockdown period and the same calendar period from the previous 6 years (OR 0.88 – CI95% 0.67-1,16 and OR 0.91; CI 95% 0.80-1.03, respectively).
To understand differences with Lazio, it cannot be excluded that in 2020 there was an information bias (3) which led to a greater accuracy in the collection data and greater precision in the case definition in the pandemic than in the previous period. This hypothesis is supported by the very low rate of SB in 2019, much lower than reported in every European region.
Thus, we conclude from our findings that no changes occurred in SB during pandemic despite the rate of first Covid 19 spread in ER was 6.2/1000, almost five times higher than the one reported in Lazio (1.3/1000) (4).
During lockdown several emergency room accesses were significantly lesser requested by patients, including gynecological referrals (5). However, obstetric clinics of the National Health System did not change their offer and Obstetrics units never interrupted their perinatal cares.
In conclusion, statistical artifact or information bias could best explain the observed transitory increase of SB in Lazio rather a direct effect of infection or a supposed reduced utilization of NHS. We hope the findings here reported will be useful for larger data collection (entire set of data is available upon request) since only big databases could reliably conclude about perinatal outcomes.
References
1. De Curtis M, Villani L, Polo A. Increase of stillbirth and decrease of late preterm infants during the COVID-19 pandemic lockdown. Arch Dis Child Fetal Neonatal Ed. 2020 Oct 30:fetalneonatal-2020-320682. doi: 10.1136/archdischild-2020-320682. Epub ahead of print. PMID: 33127736.
2. Po' G, Monari F, Zanni F, Grandi G, Lupi C, Facchinetti F; Stillbirth Emilia-Romagna Audit Group. A regional audit system for stillbirth: a way to better understand the phenomenon. BMC Pregnancy Childbirth. 2019 Aug 5;19 (1):276. doi: 10.1186/s12884-019-2432-2. PMID: 31382995; PMCID: PMC6683556.
3. Kesmodel US. Information bias in epidemiological studies with a special focus on obstetrics and gynecology. Acta Obstet Gynecol Scand. 2018 Apr;97(4):417-423
4. Dipartimento della Protezione civile – Presidenza del Consiglio dei Ministri, accessed 13 Nov 2020. < http://www.protezionecivile.gov.it>
5. Grandi G, Del Savio MC, Caroli M, Capobianco G, Dessole F, Tupponi G, Petrillo M, Succu C, Paoletti AM, Facchinetti F. The impact of COVID-19 lockdown on admission to gynecological emergency departments: Results from a multicenter Italian study. Int J Gynaecol Obstet. 2020 Jun 30. doi: 10.1002/ijgo.13289. Epub ahead of print. PMID: 32602939.
Ravaldi et al. in their letter raise two points of dispute. The first is linked to epidemiological data and the other to the fact that, according to them, a reduction in gynecological checks during pregnancy did not occur in the lockdown of spring 2020. I appreciate their engagement with the article but I disagree.
On the first point (epidemiological data), the difference between the data presented by Ravaldi and those indicated by us is linked to the fact that they mistakenly refer to older years. Ravaldi’s 2019 stillbirth is taken from the Italian Statistical Yearbook 2019, which refers to the entire 2016. Our data, obtained from the CEDAP (hospital discharge database, which records perinatal information on all newborns), are instead those of Mar-May 2019 and Mar-May 2020 (3 months of lockdown).
Furthermore, Ravaldi’s stillbirth data starting from 22 weeks were taken from the ISTAT Reproductive Health document published in 2018, which refers to 2015 data. The authors therefore cannot contest the difference in the results because they are using different data sources. A further analysis (to be published) on larger samples on all births in Lazio confirmed a significant difference between stillbirths in the period March-May 2020 compared to the same months in the years 2017-2019 (3.23 vs 1.83 per thousand, p value = 0.014) . The increase in stillbirths in the first half of 2020 was observed in numerous developed and developing countries as well as in Italy (1-...
Ravaldi et al. in their letter raise two points of dispute. The first is linked to epidemiological data and the other to the fact that, according to them, a reduction in gynecological checks during pregnancy did not occur in the lockdown of spring 2020. I appreciate their engagement with the article but I disagree.
On the first point (epidemiological data), the difference between the data presented by Ravaldi and those indicated by us is linked to the fact that they mistakenly refer to older years. Ravaldi’s 2019 stillbirth is taken from the Italian Statistical Yearbook 2019, which refers to the entire 2016. Our data, obtained from the CEDAP (hospital discharge database, which records perinatal information on all newborns), are instead those of Mar-May 2019 and Mar-May 2020 (3 months of lockdown).
Furthermore, Ravaldi’s stillbirth data starting from 22 weeks were taken from the ISTAT Reproductive Health document published in 2018, which refers to 2015 data. The authors therefore cannot contest the difference in the results because they are using different data sources. A further analysis (to be published) on larger samples on all births in Lazio confirmed a significant difference between stillbirths in the period March-May 2020 compared to the same months in the years 2017-2019 (3.23 vs 1.83 per thousand, p value = 0.014) . The increase in stillbirths in the first half of 2020 was observed in numerous developed and developing countries as well as in Italy (1-5).
On the second point, we had not indicated the precise causes of the increase in stillbirths as we did not have the data, but the most probable cause is the postponement of many medical checks that have affected all ages of life. It is true that all mothers love their children, but undoubtedly there has been a reduction in compulsory pediatric vaccinations and a postponement of many checks for fear of contracting coronavirus infection by going to hospitals and medical centers. For example, there was a reduction in emergency room activities and consequent delay in the diagnosis of various diseases, including serious ones (6-8). In the published article we never intended to blame women but we limited ourselves to observing a phenomenon.
In addition, in the study from Ravaldi et. al (9-10), the authors use a very limited sample and as they are aware there is also the risk of a sample selection bias: “Women likely to respond may have been better connected to health care and may have better access to internet and electronic facilities”.
Mario De Curtis, Leonardo Villani, Arianna Polo
References
1.Dell'Utri C, Manzoni E, Cipriani S et al. Effects of SARS Cov-2 epidemic on the obstetrical and gynecological emergency service accesses. What happened and what shall we expect now? Eur J Obstet Gynecol Reprod Biol .2020 Nov;254:64-68 July 10, 2020
2.A Khalil, von Dadelszen P, Draycott Tet al. Change in the Incidence of Stillbirth and Preterm Delivery During the COVID-19 Pandemic
3.Watson C. Stillbirth rate rises during coronavirus pandemic. Nature 2020, 585: 490
4.Mor M, Kugler N, Jauniaux E et al. Impact of the Covid-19 pandemic on excess perinatal mortality and morbidity in Israel. Am J Perinatol.2020 Dec 10, doi: 10.1055/s-0040-1721515
5. Kumari V, Mehta K, Choudhary R. Covid-19 outbreak and decreased hospitalisation of pregnant women in labour Lancet Glob Health 2020 Sep; 8(9): e1116-e1117. doi: 10.1016/S2214-109X(20)30319-3
6. Ciacchini B, Tonioli F, Marciano C et al., Reluctance to seek pediatric care during the COVID-19 pandemic and the risks of delayed diagnosis, in J. Pediatr., 2020 Jun, 29; 46(1):87, doi: 10.1186/s13052-020-00849-w;
7. Dopfer C, Wetzke M, Zychlinsky Scharff A et al., COVID-19 related reduction in pediatric emergency healthcare utilization – a concerning trend, in BMC Pediatr., 2020 Sep 7; 20(1):427, doi:10.1186/s12887-020-02303-6;
8. Lynn R. M, L Avis JL, Lenton S et al., Delayed access to care and late presentations in children during the COVID-19 pandemic: a snapshot survey of 4075 paediatricians in the UK and Ireland, in BMJ Arch. Dis. Child., 2020 Jun 25, doi: 10.1136/archdischild-2020-319848.
9. 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
10. 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
Dear Sir or Madam!
Nasal CPAP is one of the most important therapies in neonatology. Accordingly, the manufacturers of such devices are very interested in gaining market share. Not all of their "sales arguments" correspond to clinical or physical reality. This is why studies comparing different devices are so extremely important.
The authors claim to have compared three CPAP systems that are referred to as "variable-flow" devices. This refers to CPAP systems that generate their CPAP through one or more jets, corresponding to jet ventilation as it is known in laryngeal surgery. But does the Miniflow CPAP belong in this category? The Miniflow has one inspiratory and one expiratory tube and does not have a jet. Pressure is generated through the expiratory valve of a ventilator. Such CPAP devices are actually called "constant-flow" devices.
Basically, the division into variable-flow and constant-flow devices is considered very confusing and, above all, physically questionable. However, the terms are very persistent. In any case, however, the statement of the study could be supplemented. It shows not only that there is no difference between variable flow devices, but equally no difference between variable and constant flow devices.
Yours sincerely,
Martin Wald
We read with interest results from the Hypotension in Preterm Infants (HIP) trial by Dempsey et al.1 Unfortunately this multicentre randomised controlled trial (RCT) could not provide robust conclusions. Enrolment was limited to 58 of the planned 830 infants, 7% of those screened, attributed to strict inclusion criteria and recruitment challenges. This along with high inotropic usage in the restrictive group limits study power and generalisation.
Some clarification would be useful. The CONSORT diagram should label the two study arms, where imbalance in numbers not receiving the allocated intervention (6/29 vs 1/29) may warrant further analysis. The proportion with invasive lines seems low, exact reasons for exclusion/non-inclusion could be detailed, and maximum age at enrolment given.
In our published RCT 2, three blood pressure (BP) intervention protocols were compared (BP below gestational age as in HIP, more active, or less active). This single centre pilot study randomised 60 infants <29 weeks, 45% of those screened and 100% of target recruitment, with invasive BP acquired every 10 seconds for a week. The HIP trial suggests their hypotension rate of 25% is low but without BP acquisition details, comparison is difficult. Their figure showing BP following dopamine or placebo requires data variability measures.
In our study, we found higher BP was associated with lower EEG discontinuity.3 The HIP study4 did not stipulate commonly used end-organ p...
We read with interest results from the Hypotension in Preterm Infants (HIP) trial by Dempsey et al.1 Unfortunately this multicentre randomised controlled trial (RCT) could not provide robust conclusions. Enrolment was limited to 58 of the planned 830 infants, 7% of those screened, attributed to strict inclusion criteria and recruitment challenges. This along with high inotropic usage in the restrictive group limits study power and generalisation.
Some clarification would be useful. The CONSORT diagram should label the two study arms, where imbalance in numbers not receiving the allocated intervention (6/29 vs 1/29) may warrant further analysis. The proportion with invasive lines seems low, exact reasons for exclusion/non-inclusion could be detailed, and maximum age at enrolment given.
In our published RCT 2, three blood pressure (BP) intervention protocols were compared (BP below gestational age as in HIP, more active, or less active). This single centre pilot study randomised 60 infants <29 weeks, 45% of those screened and 100% of target recruitment, with invasive BP acquired every 10 seconds for a week. The HIP trial suggests their hypotension rate of 25% is low but without BP acquisition details, comparison is difficult. Their figure showing BP following dopamine or placebo requires data variability measures.
In our study, we found higher BP was associated with lower EEG discontinuity.3 The HIP study4 did not stipulate commonly used end-organ perfusion tests;5 they found abnormal cranial ultrasound (CrUSS) in 50%, but with timing unclear. Our study found lowest CrUSS abnormality rates (21%) in the active arm.
We agree that RCTs examining neonatal haemodynamics are difficult, particularly consenting parents during challenging times. None of our parents gave antenatal assent, preferring postnatal consent. Simple designs with safety-netting (echocardiography and other non-invasive measures) to detect cardiovascular compromise encourage parental and physician participation and should be considered for future trials.
References
1. Dempsey EM, Barrington KJ, Marlow N, et al. Hypotension in Preterm Infants (HIP) randomised trial. Arch Dis Chid Fetal Neonatal Ed 2021 doi: 10.1136/archdischild-2020-320241
2. Pereira SS, Sinha AK, Morris JK, et al. Blood pressure intervention levels in preterm infants: pilot randomised trial. Arch Dis Child Fetal Neonatal Ed 2018 doi: 10.1136/archdischild-2017-314159
3. Pereira SS, Kempley ST, Wertheim DF, et al. Investigation of EEG Activity Compared with Mean Arterial Blood Pressure in Extremely Preterm Infants. Frontiers in Neurology 2018;9 doi: 10.3389/fneur.2018.00087
4. Dempsey EM, Barrington KJ, Marlow N, et al. Management of hypotension in preterm infants (The HIP Trial): a randomised controlled trial of hypotension management in extremely low gestational age newborns. Neonatology 2014;105(4):275-81. doi: 10.1159/000357553
5. Stranak Z, Semberova J, Barrington K, et al. International survey on diagnosis and management of hypotension in extremely preterm babies. European journal of pediatrics 2014;173(6):793-8. doi: 10.1007/s00431-013-2251-9
We thank the authors for the comments on the Economic Evaluation of SIFT (1) and we are grateful for the opportunity to respond to their comments.
Taking each of the authors’ points in the order in which they are presented:
1. In relation to the first point about the loss to follow up and the exclusion of such patients from the analysis, we point out that we used complete case analysis and accounted for the missing patients following best practice using a multiple imputation analysis which is provided in the supplementary materials. We state the following in the paper:
“Mean total costs for all infants, adjusting for missing data using multiple imputation, are found in the online supplementary table S3. When the missing values were accounted for, faster feed increments remain more costly in comparison to slower feed increments but at a slightly higher level (£378 more) per infant, reflecting the high level of uncertainty in the difference in costs, especially with regard to the healthcare resource use after discharge estimated by the multiple imputation” (last paragraph of methods))
2. In relation to the authors second concern, whilst death was slightly higher in the slower feeds arm during initial hospital stay there are two important points in response to this. First, we clarify that by definition economic analysis is not an exercise in accountancy where death is assumed to incur a zero cost, because economic evaluation focuses on costs and ou...
Show MoreI read with interest the economic evaluation of Speed of Increasing milk Feeds Trial (SIFT) in preterm infants presented by Tahir and colleagues.(1) While the clinical findings from the SIFT had shown short-term benefits such as lesser TPN days with faster feed increments, and was equivocal for the composite primary outcome of death and disability measured at 24 months, this analysis recommends against faster feed increments based on the cost-effectiveness analyses. The average total costs is shown to be marginally higher for subjects in this arm, with a mean difference of £267 (0.25%). I highlight below many issues that probably affect the conclusions, and the generalizability of the findings, of this economic evaluation.
First, the trial enrolled 1394 and 1399 patients in the two study arms. However, the cost data of initial hospitalization is presented for 1224 and 1246 patients in these arms. It seems that 170 and 153 patients from the two trial arms were lost to follow-up after the initial hospitalization;(2) however, the data for these subjects should not be excluded while calculating the average initial hospitalization costs per subject.
Second, more deaths during the initial hospitalization were reported in the slower increment arm and those probably lowered the average cost for this arm. It is well known that the hospitalization costs for very preterm infants that die during the neonatal period are substantially lower than those of the survivors....
Show MoreA reply to:
“Parenteral nutrition for preterm infants: Correcting for arachidonic and
docosahexaenoic acid may not suffice” by Bernard et al. regarding the publication:
Frazer LC, Martin CR. Parenteral lipid emulsions in the preterm infant: current issues
and controversies. Arch Dis Child Fetal Neonatal Ed. 2021 Jan 29: fetalneonatal-
2020-319108. doi: 10.1136/archdischild-2020-319108. Epub ahead of print. PMID:
33514630.
Lauren C. Frazer1,2, Camilia R. Martin2,3,4
1Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA
2Department of Pediatrics, Harvard Medical School, Boston, MA, USA
3Division of Translational Research, Beth Israel Deaconess Medical Center, Boston, MA, USA 4Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, MA, USA
Correspondence: cmartin1@bidmc.harvard.edu
Word Count: 216
Keywords: arachidonic acid, docosahexaenoic acid, lipid emulsions, preterm infant
Dear Editor,
We would like to thank Bernhard and colleagues for their thoughtful letter “Parenteral nutrition for preterm infants: Correcting for arachidonic and docosahexaenoic acid may not suffice” written in response to our review. The authors of the letter raised important issues regarding the lack of data surrounding the optimal balance of arachidonic (ARA) and docosahexaenoic acid (DHA) that should be administered...
Show MoreIn response to: "Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia".
We read with great interest the article by Dr Woods et al (1) that adds evidence to recent, large multicenter studies on lung ultrasound (LUS) as a predictive tool for bronchopulmonary dysplasia (BPD) (2-4). These studies, performed on a total of more than 600 infants, stem from a validated scoring system whose signs represent a progressive decrease in lung aeration in standardized ultrasound views (5). Notably, this approach is also well established in adult critical care (6).
Show MoreThe grading system adopted by Dr Woods and coworkers, has not been validated and its highest scores do not correspond to less air in the lung and therefore to a more severe pulmonary disease. Also, rather than the conventional sum of scores, Dr Woods et al. calculate a two-decimals mean score that may undermine the technique discrimination. None of these choices have ever been made for any other LUS scores, neither in neonates nor in older patients, despite ultrasound semiology and statistics needed to evaluate the predictive power are always the same (6). These factors may undermine the LUS prediction power for BPD.
Moreover, the authors needed a full ROC procedure to perform a formal diagnostic accuracy analysis, but even then, its strength would have been questionable with only 7 out 96 infants suffering from moderate-to-severe BPD (7) as target condition. This smal...
Dear authors, dear editors,
Thanks for this excellent focus on visual abilities of infants following HIE.
More than three decades ago, at a time when brain imaging of newborns with HIE was limited to ultrasound and CT scanning, we have published impairments of visual functions at an early age (Early Hum Dev 1989;20:267-279 and Neuropediatrics 1990;21:76-78) .
We could do so using standardized, outpatient methods of visual assessment.
Further use of this relatively simple tools could and should be part of assessments of infants with HIE, in particular when (diffusion weighted) MRI indicates involvement of visual tracts.
With kind regards,
Floris Groenendaal
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...
De Curtis et al reported some changes occurring in perinatal outcomes during lockdown in Lazio region, Italy. In particular, according to their data, preterm deliveries were reduced while stillbirth (SB) rate seems to be three-fold increased respect with the same period of 2019 (1).
Show MoreWe collected the same outcomes in Emilia-Romagna (ER), a northern Italian region with 4.47 million residents. Gestational age at delivery has been obtained by Birth Certificates (CedAP) while SB occurrence was collected from the Surveillance system of SB. This system is active since 2014. It records and audits, in a multidisciplinary way, each single case reported by every birth center of the Region. SB was defined according to WHO as published elsewhere together with other details of the Audit process (2).
In Emilia-Romagna, in the quarter March to May 2020, the one of the national lockdown, there were 22 SB (≥22+0 weeks) out of 6800 singletons births, for a rate of 3.24/1000. For the same quarter, in the previous 6 years, SB rate ranged from 2.86 (22/7687) in 2016 to 4.32 (31/7170) in 2019. According to one-way analysis of variance for 2014-2020 years, SB rate not changed significantly (p value >0.05 for each years of observation).
It has to be highlighted that a small number of events allow to a great variations in the rates, in a phenomenon such as SB that has a very low prevalence. For this reason, a comparison of only two points as previously done (1) could lead artif...
Ravaldi et al. in their letter raise two points of dispute. The first is linked to epidemiological data and the other to the fact that, according to them, a reduction in gynecological checks during pregnancy did not occur in the lockdown of spring 2020. I appreciate their engagement with the article but I disagree.
On the first point (epidemiological data), the difference between the data presented by Ravaldi and those indicated by us is linked to the fact that they mistakenly refer to older years. Ravaldi’s 2019 stillbirth is taken from the Italian Statistical Yearbook 2019, which refers to the entire 2016. Our data, obtained from the CEDAP (hospital discharge database, which records perinatal information on all newborns), are instead those of Mar-May 2019 and Mar-May 2020 (3 months of lockdown).
Show MoreFurthermore, Ravaldi’s stillbirth data starting from 22 weeks were taken from the ISTAT Reproductive Health document published in 2018, which refers to 2015 data. The authors therefore cannot contest the difference in the results because they are using different data sources. A further analysis (to be published) on larger samples on all births in Lazio confirmed a significant difference between stillbirths in the period March-May 2020 compared to the same months in the years 2017-2019 (3.23 vs 1.83 per thousand, p value = 0.014) . The increase in stillbirths in the first half of 2020 was observed in numerous developed and developing countries as well as in Italy (1-...
Dear Sir or Madam!
Nasal CPAP is one of the most important therapies in neonatology. Accordingly, the manufacturers of such devices are very interested in gaining market share. Not all of their "sales arguments" correspond to clinical or physical reality. This is why studies comparing different devices are so extremely important.
The authors claim to have compared three CPAP systems that are referred to as "variable-flow" devices. This refers to CPAP systems that generate their CPAP through one or more jets, corresponding to jet ventilation as it is known in laryngeal surgery. But does the Miniflow CPAP belong in this category? The Miniflow has one inspiratory and one expiratory tube and does not have a jet. Pressure is generated through the expiratory valve of a ventilator. Such CPAP devices are actually called "constant-flow" devices.
Basically, the division into variable-flow and constant-flow devices is considered very confusing and, above all, physically questionable. However, the terms are very persistent. In any case, however, the statement of the study could be supplemented. It shows not only that there is no difference between variable flow devices, but equally no difference between variable and constant flow devices.
Yours sincerely,
Martin Wald
We read with interest results from the Hypotension in Preterm Infants (HIP) trial by Dempsey et al.1 Unfortunately this multicentre randomised controlled trial (RCT) could not provide robust conclusions. Enrolment was limited to 58 of the planned 830 infants, 7% of those screened, attributed to strict inclusion criteria and recruitment challenges. This along with high inotropic usage in the restrictive group limits study power and generalisation.
Show MoreSome clarification would be useful. The CONSORT diagram should label the two study arms, where imbalance in numbers not receiving the allocated intervention (6/29 vs 1/29) may warrant further analysis. The proportion with invasive lines seems low, exact reasons for exclusion/non-inclusion could be detailed, and maximum age at enrolment given.
In our published RCT 2, three blood pressure (BP) intervention protocols were compared (BP below gestational age as in HIP, more active, or less active). This single centre pilot study randomised 60 infants <29 weeks, 45% of those screened and 100% of target recruitment, with invasive BP acquired every 10 seconds for a week. The HIP trial suggests their hypotension rate of 25% is low but without BP acquisition details, comparison is difficult. Their figure showing BP following dopamine or placebo requires data variability measures.
In our study, we found higher BP was associated with lower EEG discontinuity.3 The HIP study4 did not stipulate commonly used end-organ p...
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