Thank you for your interest in our study and your comment. When you read the 6th paragraph of the discussion of the article, you will find that we completely agree that Oxytocin could have influenced the observations. This was an observational study and moment of oxytocin was given to the discretion of the midwife. Nevertheless, we still observed umbilical circulation much longer than previously described. This study was performed in 2015, but our local guideline has recently been changed to administering oxytocin after cord clamping. A new study is currently undertaken using the same methodology.
Thank you for this interesting and highly needed piece of knowledge on physiological umbilical bllod flow. Just one remark: uterotonics were given to all women directly after birth. Oxytocin may alter umbilical blood flow due to modifications in timing and strength of contractions, and influence timing of placental disattachment. Possibly, true physiological blood flow may be still different (and continue for even longer), if medication were administered after clamping (quite possibly with no significant disadvantage for the parturient).
Dear Editor
We genuinely appreciate the readers keen interest in our paper and critical comments.1 Here are our clarifications regarding their comments.
1. The readers have perhaps misunderstood the concept of “intention to treat analysis” and “per protocol analysis”.2 Infants were analysed as they were randomized in their respective groups (intention to treat analysis). Per protocol analysis excludes the patients who deviate from the protocol. In our study, we needed to exclude the infants who were lost to follow-up and therefore their outcomes were not known. We did not exclude them because there was a protocol deviation or violation.
2. Blood dextrose levels were monitored as per unit protocol and once stable on full enteral feeds they were done once a week along with weekly routine blood evaluations up to discharge. No additional testing for blood sugars was done for the study.
3. We believe that propranolol at lower doses of 0.5mg/kg/dose 12 hourly is unlikely to affect the normal vascularization in other organs. This drug has been previously used in newborns including preterm newborns for different indications. Till date there have been no reports of deranged neuro-developmental outcome attributed to propranolol. However, we agree with the readers thoughts that long term neuro-developmental outcome would have been useful but this was beyond the scope of this study.
4. In our study, for babies born at 31-32 weeks post menstrual age the...
Dear Editor
We genuinely appreciate the readers keen interest in our paper and critical comments.1 Here are our clarifications regarding their comments.
1. The readers have perhaps misunderstood the concept of “intention to treat analysis” and “per protocol analysis”.2 Infants were analysed as they were randomized in their respective groups (intention to treat analysis). Per protocol analysis excludes the patients who deviate from the protocol. In our study, we needed to exclude the infants who were lost to follow-up and therefore their outcomes were not known. We did not exclude them because there was a protocol deviation or violation.
2. Blood dextrose levels were monitored as per unit protocol and once stable on full enteral feeds they were done once a week along with weekly routine blood evaluations up to discharge. No additional testing for blood sugars was done for the study.
3. We believe that propranolol at lower doses of 0.5mg/kg/dose 12 hourly is unlikely to affect the normal vascularization in other organs. This drug has been previously used in newborns including preterm newborns for different indications. Till date there have been no reports of deranged neuro-developmental outcome attributed to propranolol. However, we agree with the readers thoughts that long term neuro-developmental outcome would have been useful but this was beyond the scope of this study.
4. In our study, for babies born at 31-32 weeks post menstrual age the first evaluation was done by 34 weeks corrected gestational age. This is our unit protocol based on our experience (as we have seen ROP even at earlier gestation in our country). This protocol also ensures a ROP evaluation before discharge in babies who get discharged early. It does not matter whether ROP screening starts (for infants born at 31 to 32 weeks of post menstrual age) at 2 weeks or 4 weeks, as long as there is a regular periodical follow up until full vascularization of retina.
We hope that this clarifies all the concerns raised by readers.
REFERENCES:
1. Sanghvi KP, Kabra NS, Padhi P, Singh U, Dash SK, Avasthi BS. Prophylactic propranolol for prevention of ROP and visual outcome at 1 year (PreROP trial). Arch Dis Child Fetal Neonatal Ed. 2017 Jan 13. pii: fetalneonatal-2016-311548. doi: 10.1136/archdischild-2016-311548. [Epub ahead of print]
2. Intention to treat analysis and per protocol analysis: complementary information. Prescrire Int. 2012 Dec; 21(133):304-6.
Dear Sir/Madam,
We read with great interest the article by Sanghvi et al1 titled “Sanghvi KP, Kabra NS, Padhi P, Singh U, Dash SK, Avasthi BS. Prophylactic propranolol for prevention of ROP and visual outcome at 1 year (PreROP trial). Arch Dis Child Fetal Neonatal Ed. 2017 Jan 13. pii: fetalneonatal-2016-311548. doi: 10.1136/archdischild-2016-311548. [Epub ahead of print]” published in your journal which concluded that prophylactic propranolol in the prescribed dose of 1 mg/kg/day showed a decreasing trend in all outcomes of ROP though statistically not significant. We appreciate that it was a double blinded study which tried to see the effect of propranolol prophylaxis on ROP prevention in lower doses without any serious adverse events.
This trial was need based and addressed a very important and clinically relevant issue. However, we would like to address a few important concerns which came to our notice while reading through the article.
The authors state that the analysis was planned according to intention to treat(ITT) analysis, but if we see the final analysis in flow diagram, the babies which were lost to follow up are not included in the analysis. Thus, it is not a ITT but a per protocol analysis.2
The babies received study drug till 37 weeks or till complete vasularization of retina. Were blood dextrose levels monitored till this time? If the response is yes, then this would expose these tiny neonates to unnecessary daily pricks and pa...
Dear Sir/Madam,
We read with great interest the article by Sanghvi et al1 titled “Sanghvi KP, Kabra NS, Padhi P, Singh U, Dash SK, Avasthi BS. Prophylactic propranolol for prevention of ROP and visual outcome at 1 year (PreROP trial). Arch Dis Child Fetal Neonatal Ed. 2017 Jan 13. pii: fetalneonatal-2016-311548. doi: 10.1136/archdischild-2016-311548. [Epub ahead of print]” published in your journal which concluded that prophylactic propranolol in the prescribed dose of 1 mg/kg/day showed a decreasing trend in all outcomes of ROP though statistically not significant. We appreciate that it was a double blinded study which tried to see the effect of propranolol prophylaxis on ROP prevention in lower doses without any serious adverse events.
This trial was need based and addressed a very important and clinically relevant issue. However, we would like to address a few important concerns which came to our notice while reading through the article.
The authors state that the analysis was planned according to intention to treat(ITT) analysis, but if we see the final analysis in flow diagram, the babies which were lost to follow up are not included in the analysis. Thus, it is not a ITT but a per protocol analysis.2
The babies received study drug till 37 weeks or till complete vasularization of retina. Were blood dextrose levels monitored till this time? If the response is yes, then this would expose these tiny neonates to unnecessary daily pricks and pain which could lead to adverse neurological outcome.3
In this study propranolol was used to prevent ROP with the hypothesis of decreasing VEGF expression. However, this could also affect the vascularization in many other organs in preterm babies, especially the CNS.4 This study would have been more meaningful if the authors, a priori, had planned neurological assessment at 1 year.
The first examination for ROP was done at least 2 weeks and /or 31 – 32 weeks of post menstrual age. But this does not hold true for babies born at 31 or 32 weeks in whom AAP5 recommend screening at 4weeks of age and not at 2weeks as done by the authors.
1. Sanghvi KP, Kabra NS, Padhi P, Singh U, Dash SK, Avasthi BS. Prophylactic propranolol for prevention of ROP and visual outcome at 1 year (PreROP trial). Arch Dis Child Fetal Neonatal Ed. 2017 Jan 13. pii: fetalneonatal-2016-311548. doi: 10.1136/archdischild-2016-311548. [Epub ahead of print]
2. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG; CONSORT. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2012;10(1):28-55. doi: 10.1016/j.ijsu.2011.10.001. Epub 2011 Oct 12
3. Ranger M, Grunau RE. Early repetitive pain in preterm infants in relation to the developing brain. Pain Manag. 2014 Jan;4(1):57-67. doi: 10.2217/pmt.13.61
4. Haigh JJ. Role of VEGF in organogenesis. Organogenesis. 2008 Oct;4(4):247-56.
5. American Academy of Pediatrics, Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2006; 117:572–6.
We read with great interest the article by Van Zanten HA et al., published in this journal and found it very useful.1 The author rightly stated that the results reflect the real situation as data were collected for the duration infants were admitted, while nurses taking care of them and where workload varied. It will be very relevant for developing countries where nurse patient ratio is poor. But; at the same time would like to offer following comments, clarification to which would benefit the readers of this journal and will help in replication of these results in different settings also.
It is not very clear whether it was a prospective study or retrospective. In Introduction section, in the end, the author mentioned that we performed a retrospective study in preterm infants to evaluate automated fraction of inspired oxygen (FiO2) control when it was used as standard care and thus for a longer period. While in “Methods” section it is mentioned that it was a prospective observational study. These contradictory statements create confusion to the reader.
The author mentioned that during the manual period, the nurses manually titrated the supplemental oxygen following local guidelines. However; these guidelines are not given in the current paper. It would be better if clear guidelines would have been described like other studies to improve the external validity and generalizability.2
In the present study, FiO2 and pulse oximeter saturation (SpO2) were sa...
We read with great interest the article by Van Zanten HA et al., published in this journal and found it very useful.1 The author rightly stated that the results reflect the real situation as data were collected for the duration infants were admitted, while nurses taking care of them and where workload varied. It will be very relevant for developing countries where nurse patient ratio is poor. But; at the same time would like to offer following comments, clarification to which would benefit the readers of this journal and will help in replication of these results in different settings also.
It is not very clear whether it was a prospective study or retrospective. In Introduction section, in the end, the author mentioned that we performed a retrospective study in preterm infants to evaluate automated fraction of inspired oxygen (FiO2) control when it was used as standard care and thus for a longer period. While in “Methods” section it is mentioned that it was a prospective observational study. These contradictory statements create confusion to the reader.
The author mentioned that during the manual period, the nurses manually titrated the supplemental oxygen following local guidelines. However; these guidelines are not given in the current paper. It would be better if clear guidelines would have been described like other studies to improve the external validity and generalizability.2
In the present study, FiO2 and pulse oximeter saturation (SpO2) were sampled every minute, and it is quite common to have fluctuations within a period of one minute which will get missed if we have a data point of one-minute intervals and hence might give fallacious results. In this interval one might have done rapid intervention during hypoxemia in the manual group, hence that hypoxemia episode might get masked with intervention. A study by Van Kaam et al using the same technology and lesser interval (5 seconds) found that automated control reduced hypoxemia.2
The author didn’t mention about sickness status of babies enrolled in the study. Babies with persistent pulmonary arterial hypertension and patent ductus arteriosus may have a difference in pre and postductal saturation. So, in such cases probe site will have implication. What was probe site chosen in babies in this study? Also; the author should mention whether sickness levels in both groups were similar or not.
The study concludes that with the implementation of automated oxygen control there was a significant reduction in hypoxemia, but not hypoxemia. It seems to be oversimplification of results. Carefully looking at the results there will be concern that more babies were having SpO2<90%, (median (IQR) 8.6 (7.2–11.7) 15.1 (14.0–21.1) <0.0001) in the automated group. And this finding is consistent with most of the studies done on automated oxygen control.3 Possible reason for this finding may be the human behavior to accept high saturation or an inherent problem with the design of automated algorithm which tends to keep saturation on the lower side of target range and hence more prone to hypoxemia.4 The cumulative effect of preventing hyperoxemia (>95%) and allowing lower saturations (85-89%) in automated group, on clinical outcomes needs to be evaluated.
As of now from various studies done using this algorithm, it seems that automated oxygenation control systems cannot prevent the occurrence of episodes of hypoxemia. Although studies have shown that it reduces the duration or severity and severity of hypoxemia episodes by increasing Fio2 but still there is need of development in an algorithm to prevent these episodes.
Competing interests: None
Source of funding: None
References:
1 Van Zanten H, Kuypers K, Stenson B et al. The effect of implementing an automated oxygen control on oxygen saturation in preterm infants. Archives of Disease in Childhood - Fetal and Neonatal Edition 2017;:fetalneonatal-2016-312172. doi:10.1136/archdischild-2016-312172
2 van Kaam A, Hummler H, Wilinska M et al. Automated versus Manual Oxygen Control with Different Saturation Targets and Modes of Respiratory Support in Preterm Infants. The Journal of Pediatrics 2015;167:545-550.e2. doi:10.1016/j.jpeds.2015.06.012
3 Claure NBancalari E. Oxygen Saturation Targeting by Automatic Control of Inspired Oxygen in Premature Infants. NeoReviews 2015;16:e406-e412. doi:10.1542/neo.16-7-e406
4 Bancalari EClaure N. Control of Oxygenation During Mechanical Ventilation in the Premature Infant. Clinics in Perinatology 2012;39:563-572. doi:10.1016/j.clp.2012.06.013
We read with great interest the article by Van Zanten HA et al., published in this journal and found the results impressive.[1] However, we have certain observations about the conduct of the study
Even though the authors state that this report was part of a quality improvement initiative in their NICU, the authors have neither reported the results in the format suitable for a quality improvement study nor have clearly stated the design; at the end of introduction they seem to mention that this was a retrospective data analysis; whereas, in the first line of the methods they state the design as a prospective observational study. Even though the automatic oxygen controller group would not have been affected much by any one of the design, the impact would have been in the manual group, keeping especially the training of the NICU staff in mind. It’s also worth emphasizing here that the authors mention about the local guidelines practiced for manual titration of supplemental oxygen based on the saturations, for the sake of external validity.[2]
Minute wise data points used in this study may have significantly underestimated the hypoxemic episodes and thereby the proportion of times an infant remained in the ‘below target range’ saturations. In a logical sense, manual titration would have happened sooner than expected for a hypoxemic event and hence would not have been captured if more frequent data points are not considered. Using the same technology and a lesser in...
We read with great interest the article by Van Zanten HA et al., published in this journal and found the results impressive.[1] However, we have certain observations about the conduct of the study
Even though the authors state that this report was part of a quality improvement initiative in their NICU, the authors have neither reported the results in the format suitable for a quality improvement study nor have clearly stated the design; at the end of introduction they seem to mention that this was a retrospective data analysis; whereas, in the first line of the methods they state the design as a prospective observational study. Even though the automatic oxygen controller group would not have been affected much by any one of the design, the impact would have been in the manual group, keeping especially the training of the NICU staff in mind. It’s also worth emphasizing here that the authors mention about the local guidelines practiced for manual titration of supplemental oxygen based on the saturations, for the sake of external validity.[2]
Minute wise data points used in this study may have significantly underestimated the hypoxemic episodes and thereby the proportion of times an infant remained in the ‘below target range’ saturations. In a logical sense, manual titration would have happened sooner than expected for a hypoxemic event and hence would not have been captured if more frequent data points are not considered. Using the same technology and a lesser interval (5 seconds) Van Kaam et al had shown aptly that automated control reduced hypoxemia.[2]
Comparative data on the clinical morbidities such as pulmonary artery hypertension and patent ductus arteriosus would be important as these morbidities if differentially distributed in the comparison groups, would have affected the hypoxemic episodes and proportion of time below the target range.
While concluding, the authors seem to have conveniently avoided describing the significant time spent below the target range in the automated control group. Even though this could have been due to the inherent human behavioral pattern of responding faster to lower saturations, an inbuilt error in the closed loop algorithm with a differential sensitivity towards lower saturations could have also played a role in such phenomenon.[3] For a reader, a strong message would be that even though the control is automated, a close look into the algorithm of the manufacturer is immediately required to avoid spending more time below the target range, especially when one does not know the impact of such ‘below target range’ saturations on long-term neurodevelopmental and pulmonary outcomes.
Competing interests: None
Source of funding: None
References:
1 Van Zanten H, Kuypers K, Stenson B et al. The effect of implementing an automated oxygen control on oxygen saturation in preterm infants. Archives of Disease in Childhood - Fetal and Neonatal Edition 2017fetalneonatal-2016-312172. doi:10.1136/archdischild-2016-312172
2 van Kaam A, Hummler H, Wilinska M et al. Automated versus Manual Oxygen Control with Different Saturation Targets and Modes of Respiratory Support in Preterm Infants. The Journal of Pediatrics 2015;167:545-550.e2. doi:10.1016/j.jpeds.2015.06.012
3 Bancalari E, Claure N. Control of Oxygenation During Mechanical Ventilation in the Premature Infant. Clinics in Perinatology 2012;39:563-572. doi:10.1016/j.clp.2012.06.013
We read with great interest the article by Sinead J Glackin et al, published in this journal and found the results impressive.[1]. However, we have certain observations about the conduct of the study.
Even though it was a randomized controlled trial and authors mentioned that oral feeds were offered in both groups at least once every 72 hours and additional feeds were offered when neonates demonstrated feeding cues but they didn’t mention about the exact feeding schedule like frequency of oral feeding, volume per feed and rate of hike of feeds in each group. This bears an important implication on the primary outcome as well as the external validity of the study. If there is no well-defined policy then there will be individualization of practice and lot of bias in the study despite randomization. It’s also worth emphasizing here that the authors should have mentioned about the local guidelines practiced for feed hiking and definition of feed intolerance, for the sake of external validity.
Despite being eligible and in a trial authors could give first oral feed 9-10 days after the enrollment. The reason for the delay of initiation of oral feeds for so many days despite eligibility is not very clear. Even in a randomized trail when we fail to initiate oral feeds before 33-34 weeks of corrected gestational age, it will not be feasible in routine practice. So, before using these results in clinical practice we should have strong evidence for the age of initiation of...
We read with great interest the article by Sinead J Glackin et al, published in this journal and found the results impressive.[1]. However, we have certain observations about the conduct of the study.
Even though it was a randomized controlled trial and authors mentioned that oral feeds were offered in both groups at least once every 72 hours and additional feeds were offered when neonates demonstrated feeding cues but they didn’t mention about the exact feeding schedule like frequency of oral feeding, volume per feed and rate of hike of feeds in each group. This bears an important implication on the primary outcome as well as the external validity of the study. If there is no well-defined policy then there will be individualization of practice and lot of bias in the study despite randomization. It’s also worth emphasizing here that the authors should have mentioned about the local guidelines practiced for feed hiking and definition of feed intolerance, for the sake of external validity.
Despite being eligible and in a trial authors could give first oral feed 9-10 days after the enrollment. The reason for the delay of initiation of oral feeds for so many days despite eligibility is not very clear. Even in a randomized trail when we fail to initiate oral feeds before 33-34 weeks of corrected gestational age, it will not be feasible in routine practice. So, before using these results in clinical practice we should have strong evidence for the age of initiation of feeds. Most of the units practice cue based feeding initiation and hiking. There is enough evidence to suggest that non-nutritive sucking reduces the time infants need to transition from tube to full oral feeding,[2] here it is worth to mention about this practice in the study population.
A prospective cohort study by Shetty et al,[3] is inappropriately mentioned as case series at multiple places in the article.
Overall this trial succeeds in giving a clear message on feasibility and safety of oral feeding while on nasal CPAP or high flow nasal cannula.
Competing interests: None
Source of funding: None
References:
1. Glackin SJ, O’Sullivan A, George S, et al. High flow nasal cannula versus NCPAP, duration to full oral feeds in preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2017;102:F329–32.
2. Foster JP, Psaila K, Patterson T. Non-nutritive sucking for increasing physiologic stability and nutrition in preterm infants. Cochrane Database Syst Rev. 2016 Oct 4;10:CD001071.
3. Shetty S, Hunt K, Douthwaite A, et al. High-flow nasal cannula oxygen and nasal continuous positive airway pressure and full oral feeding in infants with bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed. 2016;101:F408-411.
We read with great interest the article by Lianne Verbeek et al, published in this journal and found the results impressive however we didn’t agree with the conclusion drawn by the author.[1] In present study authors concluded that delayed cord clamping may not be advisable in second-born monochorionic twins after vaginal birth due to polycythemia and associated complications. We don’t agree with the authors in this regard. In this study there was no difference in symptomatic polycythemia, need for the partial exchange or mortality. There is no mention about hypoglycemia and jaundice in the study population. American heart association guidelines for neonatal resuscitation[2] recommends delayed cord clamping (DCC) for all preterms who didn’t require resuscitation in view of their potential benefits (decreased mortality, higher blood pressure and blood volume, less need for postnatal blood transfusion, less intraventricular hemorrhages and less risk of necrotizing enterocolitis) which outweighs minor possible complications (increased risks of polycythemia and jaundice). We suggest that till there is enough evidence to change practice we should follow DCC for first as well as second order twin in preterm as well as term babies.
Despite so many studies[1,3,4] on this issue, we are still at the stage of hypothesis only. For better understanding, there is need of large prospective study which keeps a record of the timing of cord clamping to accept/ refute the hypothesis an...
We read with great interest the article by Lianne Verbeek et al, published in this journal and found the results impressive however we didn’t agree with the conclusion drawn by the author.[1] In present study authors concluded that delayed cord clamping may not be advisable in second-born monochorionic twins after vaginal birth due to polycythemia and associated complications. We don’t agree with the authors in this regard. In this study there was no difference in symptomatic polycythemia, need for the partial exchange or mortality. There is no mention about hypoglycemia and jaundice in the study population. American heart association guidelines for neonatal resuscitation[2] recommends delayed cord clamping (DCC) for all preterms who didn’t require resuscitation in view of their potential benefits (decreased mortality, higher blood pressure and blood volume, less need for postnatal blood transfusion, less intraventricular hemorrhages and less risk of necrotizing enterocolitis) which outweighs minor possible complications (increased risks of polycythemia and jaundice). We suggest that till there is enough evidence to change practice we should follow DCC for first as well as second order twin in preterm as well as term babies.
Despite so many studies[1,3,4] on this issue, we are still at the stage of hypothesis only. For better understanding, there is need of large prospective study which keeps a record of the timing of cord clamping to accept/ refute the hypothesis and with good follow up to look for differences in need of blood transfusion in postnatal age and neurodevelopmental outcome.
Competing interests: None
Source of funding: None
References:
1. Verbeek L, Zhao DP, Middeldorp JM, et al. Haemoglobin discordances in twins: due to differences in timing of cord clamping? Arch Dis Child Fetal Neonatal Ed. 2017;102: F324–8.
2. Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132: S543-560.
3. Verbeek L, Zhao DP, Te Pas AB, et al. Hemoglobin Differences in Uncomplicated Monochorionic Twins in Relation to Birth Order and Mode of Delivery. Twin Res Hum Genet Off J Int Soc Twin Stud. 2016;19:241–5.
4. Lopriore E, Sueters M, Middeldorp JM, et al. Haemoglobin differences at birth in monochorionic twins without chronic twin-to-twin transfusion syndrome. Prenat Diagn. 2005;25:844–50.
Dear Editor,
We read with interest the article by Verbeek L. et al [1], showing that
the second-born twin has higher levels of hemoglobin (Hb) than first-born
co-twins after vaginal delivery (VD; Hb differential effect does not occur
in twins delivered by Caesarean section. Since Hb difference is present in
both uncomplicated monochorionic (MC) and dichorionic (DC) twin pairs,
authors focused on the time difference of umbi...
Dear Editor,
We read with interest the article by Verbeek L. et al [1], showing that
the second-born twin has higher levels of hemoglobin (Hb) than first-born
co-twins after vaginal delivery (VD; Hb differential effect does not occur
in twins delivered by Caesarean section. Since Hb difference is present in
both uncomplicated monochorionic (MC) and dichorionic (DC) twin pairs,
authors focused on the time difference of umbilical cord clampings (UCC)
for the two twins, rather than vascular anastomoses (absent in DC twins).
Precise timing data unfortunately were not recorded.
However, beside UCC timing, other factors should be taken into account for
the VD management. Recent observations have provided compelling evidence
demonstrating that UCC timing is not the only determinant of net placental
-to-infant blood transfusion [2]; uterine contractions and lung aeration
result to be determinant factors influencing umbilical artery and venous
blood flows[2]. Specifically the uterine contractions during the third
stage of labor significantly increase the placental-to-neonatal gradient
and may facilitate 50% of placental transfusion [3]; such effect is also
reported in single term neonates when the "two step" head-to-body delivery
method is used [4].
In our opinion, uterine contractions can affect the placental transfusion
more than UCC timing in the vaginally born twins: the second-born twin is
exposed to the contractions that lead to the birth of the first twin!
These additional contractions can increase the placental transfusion and
the risk of polycithemia both in DC and MC twins; moreover, in second-born
MC twin, contractions can determine acute inter-twin blood transfusion
through placental vascular anastomoses.
In agreement with authors [1], targeted studies in the twins delivered
vaginally should be carried out to establish the optimal UCC timing;
anyway we recommend evaluating also the effect of uterine contractions as
well as medications administered to the mothers, such as oxytocin-like
components.
REFERENCES
1. Verbeek L, Zhao DP, Middeldorp JM, et al. Haemoglobin discordances in
twins: due to differences in timing of cord clamping? Arch Dis Child Fetal
Neonatal Ed. 2016 Dec 9. pii: fetalneonatal-2016-311822.
2. Hooper SB, Binder-Heschl C, Polglase GR, et al. The timing of umbilical
cord clamping at birth: physiological considerations. Matern Health
Neonatol Perinatol. 2016 Jun 13;2:4. Review.
3. Katheria AC, Lakshminrusimha S, Rabe H, et al . Placental transfusion:
a review. J Perinatol. 2016 Sep 22.
4. Zanardo V, Gabrieli C, de Luca F, et al . Head-to-body delivery by "two
-step" approach: effect on cord blood hematocrit. J Matern Fetal Neonatal
Med. 2013 Aug;26(12):1234-8.
We thank Dr. de Carolis and co-authors for their interest in our study on hemoglobin (Hb) level differences at birth in uncomplicated monochorionic and dichorionic twins. We found that second-born monochorionic and dichorionic twins have higher Hb levels at birth compared to first-born twins when delivered vaginally. Since Hb differences at birth are also present in dichorionic twins, we hypothesized that Hb differences might be due to differences in timing of cord clamping, rather than placental vascular anastomoses.
Several studies demonstrated that delayed cord clamping is associated with higher Hb levels at birth compared to early cord clamping[1], the physiological mechanism is not well understood. Although we agree that other factors may influence Hb levels during delayed cord clamping at birth, the effect of uterine contractions may be not as clear-cut as dr. de Carolis and co-authors suggest. It has been suggested that uterine contractions influence placento-fetal transfusion. However, Westgate et al. found that uterine contractions primarily cause a pressure-induced, differential reduction in flow in both vessels as well as a reduction in uterine flow.[2] This was also observed in lambs, where oxytocin-induced contractions led to a cessation of the umbilical venous flow and the flow in the umbilical artery was greatly reduced resulting in retrograde flow during diastole.[3]
We thank Dr. de Carolis and co-authors for their interest in our study on hemoglobin (Hb) level differences at birth in uncomplicated monochorionic and dichorionic twins. We found that second-born monochorionic and dichorionic twins have higher Hb levels at birth compared to first-born twins when delivered vaginally. Since Hb differences at birth are also present in dichorionic twins, we hypothesized that Hb differences might be due to differences in timing of cord clamping, rather than placental vascular anastomoses.
Several studies demonstrated that delayed cord clamping is associated with higher Hb levels at birth compared to early cord clamping[1], the physiological mechanism is not well understood. Although we agree that other factors may influence Hb levels during delayed cord clamping at birth, the effect of uterine contractions may be not as clear-cut as dr. de Carolis and co-authors suggest. It has been suggested that uterine contractions influence placento-fetal transfusion. However, Westgate et al. found that uterine contractions primarily cause a pressure-induced, differential reduction in flow in both vessels as well as a reduction in uterine flow.[2] This was also observed in lambs, where oxytocin-induced contractions led to a cessation of the umbilical venous flow and the flow in the umbilical artery was greatly reduced resulting in retrograde flow during diastole.[3]
Reference List
1. McDonald SJ, Middleton P, Dowswell T, Morris PS: Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev 2013;CD004074.
2. Westgate JA, Wibbens B, Bennet L, Wassink G, Parer JT, Gunn AJ: The intrapartum deceleration in center stage: a physiologic approach to the interpretation of fetal heart rate changes in labor. Am J Obstet Gynecol 2007;197:236-11.
3. Hooper SB, Binder-Heschl C, Polglase GR, Gill AW, Kluckow M, Wallace EM, Blank D, Te Pas AB: The timing of umbilical cord clamping at birth: physiological considerations. Matern Health Neonatol Perinatol 2016;2:4.
Thank you for your interest in our study and your comment. When you read the 6th paragraph of the discussion of the article, you will find that we completely agree that Oxytocin could have influenced the observations. This was an observational study and moment of oxytocin was given to the discretion of the midwife. Nevertheless, we still observed umbilical circulation much longer than previously described. This study was performed in 2015, but our local guideline has recently been changed to administering oxytocin after cord clamping. A new study is currently undertaken using the same methodology.
Thank you for this interesting and highly needed piece of knowledge on physiological umbilical bllod flow. Just one remark: uterotonics were given to all women directly after birth. Oxytocin may alter umbilical blood flow due to modifications in timing and strength of contractions, and influence timing of placental disattachment. Possibly, true physiological blood flow may be still different (and continue for even longer), if medication were administered after clamping (quite possibly with no significant disadvantage for the parturient).
Dear Editor
Show MoreWe genuinely appreciate the readers keen interest in our paper and critical comments.1 Here are our clarifications regarding their comments.
1. The readers have perhaps misunderstood the concept of “intention to treat analysis” and “per protocol analysis”.2 Infants were analysed as they were randomized in their respective groups (intention to treat analysis). Per protocol analysis excludes the patients who deviate from the protocol. In our study, we needed to exclude the infants who were lost to follow-up and therefore their outcomes were not known. We did not exclude them because there was a protocol deviation or violation.
2. Blood dextrose levels were monitored as per unit protocol and once stable on full enteral feeds they were done once a week along with weekly routine blood evaluations up to discharge. No additional testing for blood sugars was done for the study.
3. We believe that propranolol at lower doses of 0.5mg/kg/dose 12 hourly is unlikely to affect the normal vascularization in other organs. This drug has been previously used in newborns including preterm newborns for different indications. Till date there have been no reports of deranged neuro-developmental outcome attributed to propranolol. However, we agree with the readers thoughts that long term neuro-developmental outcome would have been useful but this was beyond the scope of this study.
4. In our study, for babies born at 31-32 weeks post menstrual age the...
Dear Sir/Madam,
We read with great interest the article by Sanghvi et al1 titled “Sanghvi KP, Kabra NS, Padhi P, Singh U, Dash SK, Avasthi BS. Prophylactic propranolol for prevention of ROP and visual outcome at 1 year (PreROP trial). Arch Dis Child Fetal Neonatal Ed. 2017 Jan 13. pii: fetalneonatal-2016-311548. doi: 10.1136/archdischild-2016-311548. [Epub ahead of print]” published in your journal which concluded that prophylactic propranolol in the prescribed dose of 1 mg/kg/day showed a decreasing trend in all outcomes of ROP though statistically not significant. We appreciate that it was a double blinded study which tried to see the effect of propranolol prophylaxis on ROP prevention in lower doses without any serious adverse events.
This trial was need based and addressed a very important and clinically relevant issue. However, we would like to address a few important concerns which came to our notice while reading through the article.
The authors state that the analysis was planned according to intention to treat(ITT) analysis, but if we see the final analysis in flow diagram, the babies which were lost to follow up are not included in the analysis. Thus, it is not a ITT but a per protocol analysis.2
The babies received study drug till 37 weeks or till complete vasularization of retina. Were blood dextrose levels monitored till this time? If the response is yes, then this would expose these tiny neonates to unnecessary daily pricks and pa...
Show MoreWe read with great interest the article by Van Zanten HA et al., published in this journal and found it very useful.1 The author rightly stated that the results reflect the real situation as data were collected for the duration infants were admitted, while nurses taking care of them and where workload varied. It will be very relevant for developing countries where nurse patient ratio is poor. But; at the same time would like to offer following comments, clarification to which would benefit the readers of this journal and will help in replication of these results in different settings also.
Show MoreIt is not very clear whether it was a prospective study or retrospective. In Introduction section, in the end, the author mentioned that we performed a retrospective study in preterm infants to evaluate automated fraction of inspired oxygen (FiO2) control when it was used as standard care and thus for a longer period. While in “Methods” section it is mentioned that it was a prospective observational study. These contradictory statements create confusion to the reader.
The author mentioned that during the manual period, the nurses manually titrated the supplemental oxygen following local guidelines. However; these guidelines are not given in the current paper. It would be better if clear guidelines would have been described like other studies to improve the external validity and generalizability.2
In the present study, FiO2 and pulse oximeter saturation (SpO2) were sa...
We read with great interest the article by Van Zanten HA et al., published in this journal and found the results impressive.[1] However, we have certain observations about the conduct of the study
Show MoreEven though the authors state that this report was part of a quality improvement initiative in their NICU, the authors have neither reported the results in the format suitable for a quality improvement study nor have clearly stated the design; at the end of introduction they seem to mention that this was a retrospective data analysis; whereas, in the first line of the methods they state the design as a prospective observational study. Even though the automatic oxygen controller group would not have been affected much by any one of the design, the impact would have been in the manual group, keeping especially the training of the NICU staff in mind. It’s also worth emphasizing here that the authors mention about the local guidelines practiced for manual titration of supplemental oxygen based on the saturations, for the sake of external validity.[2]
Minute wise data points used in this study may have significantly underestimated the hypoxemic episodes and thereby the proportion of times an infant remained in the ‘below target range’ saturations. In a logical sense, manual titration would have happened sooner than expected for a hypoxemic event and hence would not have been captured if more frequent data points are not considered. Using the same technology and a lesser in...
We read with great interest the article by Sinead J Glackin et al, published in this journal and found the results impressive.[1]. However, we have certain observations about the conduct of the study.
Show MoreEven though it was a randomized controlled trial and authors mentioned that oral feeds were offered in both groups at least once every 72 hours and additional feeds were offered when neonates demonstrated feeding cues but they didn’t mention about the exact feeding schedule like frequency of oral feeding, volume per feed and rate of hike of feeds in each group. This bears an important implication on the primary outcome as well as the external validity of the study. If there is no well-defined policy then there will be individualization of practice and lot of bias in the study despite randomization. It’s also worth emphasizing here that the authors should have mentioned about the local guidelines practiced for feed hiking and definition of feed intolerance, for the sake of external validity.
Despite being eligible and in a trial authors could give first oral feed 9-10 days after the enrollment. The reason for the delay of initiation of oral feeds for so many days despite eligibility is not very clear. Even in a randomized trail when we fail to initiate oral feeds before 33-34 weeks of corrected gestational age, it will not be feasible in routine practice. So, before using these results in clinical practice we should have strong evidence for the age of initiation of...
We read with great interest the article by Lianne Verbeek et al, published in this journal and found the results impressive however we didn’t agree with the conclusion drawn by the author.[1] In present study authors concluded that delayed cord clamping may not be advisable in second-born monochorionic twins after vaginal birth due to polycythemia and associated complications. We don’t agree with the authors in this regard. In this study there was no difference in symptomatic polycythemia, need for the partial exchange or mortality. There is no mention about hypoglycemia and jaundice in the study population. American heart association guidelines for neonatal resuscitation[2] recommends delayed cord clamping (DCC) for all preterms who didn’t require resuscitation in view of their potential benefits (decreased mortality, higher blood pressure and blood volume, less need for postnatal blood transfusion, less intraventricular hemorrhages and less risk of necrotizing enterocolitis) which outweighs minor possible complications (increased risks of polycythemia and jaundice). We suggest that till there is enough evidence to change practice we should follow DCC for first as well as second order twin in preterm as well as term babies.
Show MoreDespite so many studies[1,3,4] on this issue, we are still at the stage of hypothesis only. For better understanding, there is need of large prospective study which keeps a record of the timing of cord clamping to accept/ refute the hypothesis an...
Dear Editor, We read with interest the article by Verbeek L. et al [1], showing that the second-born twin has higher levels of hemoglobin (Hb) than first-born co-twins after vaginal delivery (VD; Hb differential effect does not occur in twins delivered by Caesarean section. Since Hb difference is present in both uncomplicated monochorionic (MC) and dichorionic (DC) twin pairs, authors focused on the time difference of umbi...
We thank Dr. de Carolis and co-authors for their interest in our study on hemoglobin (Hb) level differences at birth in uncomplicated monochorionic and dichorionic twins. We found that second-born monochorionic and dichorionic twins have higher Hb levels at birth compared to first-born twins when delivered vaginally. Since Hb differences at birth are also present in dichorionic twins, we hypothesized that Hb differences might be due to differences in timing of cord clamping, rather than placental vascular anastomoses.
Several studies demonstrated that delayed cord clamping is associated with higher Hb levels at birth compared to early cord clamping[1], the physiological mechanism is not well understood. Although we agree that other factors may influence Hb levels during delayed cord clamping at birth, the effect of uterine contractions may be not as clear-cut as dr. de Carolis and co-authors suggest. It has been suggested that uterine contractions influence placento-fetal transfusion. However, Westgate et al. found that uterine contractions primarily cause a pressure-induced, differential reduction in flow in both vessels as well as a reduction in uterine flow.[2] This was also observed in lambs, where oxytocin-induced contractions led to a cessation of the umbilical venous flow and the flow in the umbilical artery was greatly reduced resulting in retrograde flow during diastole.[3]
Reference List
1. McDonald SJ, Middleton P, Dowswell T, Morris PS: Eff...
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