Diazoxide for hyperinsulinism? Not so fast

Infants with congential persistent hyperinsulinism have been treated for years with diazoxide, well before many of the genetic mutations underlying the condition were known (there are now at least 14 of them!). Diazoxide seems to be relatively well tolerated in this group of patients, although they do not all respond; they are otherwise difficult to treat, and may eventually need other interventions.

There seems to be an increasing use of diazoxide among infants with transient hyperinsulinism also, several recent large cohorts have been published, and there are increasing reports of adverse secondary events. The most common serious event is pulmonary hypertension, which seems to be more common in this group than with genetic congenital hyperinsulinism. (Thornton P, et al. Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism. Horm Res Paediatr. 2019;91(1):25-32.) That study showed an 8% incidence of pulmonary hypertension in the stress-hyperinsulinism group and a 1% incidence with genetic hyperinsulinism.  Fluid retention is also frequent, and a case of profound persistent hypotension leading to PVL in a preterm baby has been reported (it was first used as an anti-hypertensive agent that was accidentally noticed to cause hyperglycemia). In rats it dilates the ductus arteriosus.

In the largest cohort study of over 1000 treated babies, 12% of babies needed new oxygen support after treatment was started, 5% had to be intubated and 14% were started on diuretics. In other reports babies have become extremely unwell with right vetricular failure due to pulmonary hypertension. In that same cohort 92% of the babies were weaned off diazoxide before discharge from the hospital, which makes me wonder if they really needed it.

Many babies with so-called perinatal stress hypoglycemia can be easily managed with extra glucose, but for some their course is prolonged and complex; In some of those babies it may be that diazoxide is a reasonable solution, but right now it is impossible to calculate the balance of benefits and risks. I wonder if the current increase in use is really justifiable with a medication that has these toxicities, we really need much better studies. It is a common enough problem that children with ‘perinatal stress hyperinsulinism’ that persists could be randomized, perhaps after 5 days or so when the risk seems to be less, and to avoid use in teh preterm or in infants with respiratory distress as they seem to have higher risks. (Herrera A, et al. Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. J Clin Endocrinol Metab. 2018;103(12):4365-72)

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Donor human milk for congenital heart disease?

Newborns with serious Congenital Heart Disease are at risk of intestinal injury which may present in a similar fashion to Necrotising Enterocolitis (NEC). Our local guidelines for eligibility for donor milk from our provincial milk bank include infants with significant CHD, based on the fairly robust data about NEC prevention by donor human milk, compared to formula, as a supplement to maternal milk among very preterm infants.

But is “NEC” in infants with CHD the same disease? Should we expect donor human milk to be protective for these infants?

The neonatal gut has a limited number of responses to injury, I have seen, for example, in the fairly recent past, 2 preterm babies who had a typical NEC clinical presentation, with clear pneumatosis on abdominal x-ray, who both turned out to have strangulated small intestine, one from a malrotation and the other from an internal hernia, when operated (both did well).

Diagnostic criteria for NEC in the term infant are not clear, but most studies have used the Bell criteria developed for preterm infants, and, as I am suggesting, the pathophysiology is probably different. In the preterm there is evidence that immaturity of Paneth cell development (as one example) is important, but there is no reason to believe that they are immature in babies born at term with CHD.

One of the best studies of incidence is a very recently published multicenter cohort study with over 38,000 newborns with CHD, 1,448 of them developed NEC (Spinner JA, et al. Necrotizing Enterocolitis and Associated Mortality in Neonates With Congenital Heart Disease: A Multi-Institutional Study. Pediatr Crit Care Med. 2019). The lowest frequency among infants included was for transposition of the great vessels (TGV) at 2.1%, the most frequent was among infants with hypoplastic left heart syndrome (HLHS), 5.5% :

That study noted that infants who were preterm, in addition to their CHD, had a substantially increased risk, being born before 37 weeks gestation increased the Odds of developing NEC by 1.6 among HLHS, 3.5 for TOF, and 6.5 for TGA.

A new observational study suggests that donor human milk may be useful for prevention of NEC among these infants. Cognata A, et al. Human Milk Use in the Preoperative Period Is Associated with a Lower Risk for Necrotizing Enterocolitis in Neonates with Complex Congenital Heart Disease. J Pediatr. 2019. Among 548 infants at the Texas children’s hospital in Houston, there were 1/3 who did not get fed pre-operatively. That is a frequent practice elsewhere also, for which there is really no good evidence, but concerns about gut perfusion in HLHS or severe co-arctation are reasonable, even if the ductus is wide-open on echo. They had 18 total cases of pre-operative NEC, so a limited power to say very much. Among the remaining infants, who did get fed, if they received only unfortified human milk (maternal or donor) which was about 200 babies, they had a lower incidence of NEC, only 2 cases. On multivariate analysis, human milk feeding was protective (OR 0.17, 95% CI 0.04-0.84).

This is certainly suggestive data; is there any reason to not just give donor milk, whenever supplements are required, for an infant hospitalised with CHD? The big “problem” as I see it is the large amount of milk such infants require compared to a small preterm infant. Depending on how your milk banks are organised, and how much milk they have available, three 4 kg babies with CHD could quickly drain the stocks, leaving nothing for the next thirty 400g babies!

I think the best solution is probably to ensure that preterm infants with CHD get human milk, whenever possible. If you have plenty of donor milk available, at a reasonable cost (it certainly isn’t cheap to screen and process) then giving full-term babies pasteurized donor milk is almost certainly harmless, and might reduce cases of NEC. However, a large enough RCT of donor human milk supplementation among full term babies with CHD could settle the question permanently.



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Where does sepsis come from?

One of the findings of the recent SIFT trial was that although the babies in the fast feeding group had shorter duration of parenteral nutrition, TPN, (and presumably of central lines), they did not have less late-onset sepsis, LOS. Why not?

The difference in duration of TPN was only 2 days (median 9 days with fast feeding, 11 days with slow) which maybe didn’t give enough power to show a difference in LOS. But both culture positive sepsis and clinically suspected sepsis were almost identical in the 2 groups.

In the CNN 2017 report, LOS incidence for infants up to and including 32 weeks gestation varied between about 1.7 and 5 infections per 1000 patient days, central-line associated blood stream infections, CLABSI, varied between 1.9 and 12 per 1000 central line days. So a much greater variation in CLABSI than in LOS overall. 75% of CoNS infections were CLABSI, compared to about 64% of nonCoNS infections, in other words the bacteriologic profile of CLABSI differs from infections when no line is present, but many “CLABSI” are caused by enteric gram negative organisms.

In the recently available 2018 CNN report if you look at the 2 figures for comparisons of LOS and for CLABSI between centers, you can see that the site with the highest CLABSI rates did not have a very high rate for overall LOS, in fact they were exactly on the line for an average rate for overall LOS, whereas the site with the highest LOS rate at 6.9 per 1000 patient days had a lower than average rate of CLABSI (4.7 per 1000 catheter days, compared to 6.6 for the network as a whole).

Our quality control initiatives for reducing LOS have been multi-pronged, but have included a strong movement to try and reduce CLABSI, we, in my hospital, now take out central lines when enteral feeding is established at more than 120 mL/kg/d, for example, which leads to a short period with less nutrition. But, in fact, as mentioned most organisms causing late-onset sepsis, other than CoNS, are enteric bacteria, and they can usually be found in the individual baby’s GI tract prior to that baby developing an infection.

There are many studies supporting this finding, here are a couple of recent examples and a review article.

Stewart CJ, et al. Longitudinal development of the gut microbiome and metabolome in preterm neonates with late onset sepsis and healthy controls. Microbiome. 2017;5(1):75.

Taft DH, et al. Center Variation in Intestinal Microbiota Prior to Late-Onset Sepsis in Preterm Infants. PloS One. 2015;10(6):e0130604.

Masi AC, Stewart CJ. The role of the preterm intestinal microbiome in sepsis and necrotising enterocolitis. Early Hum Dev. 2019;138:104854.

Our emphasis on central lines as a risk for sepsis is partly misplaced I think. If I reduce CLABSI (by taking out central lines faster, for example) but don’t impact LOS, then I haven’t benefitted the babies at all. Especially if the rate of LOS goes up, because of skin disruption from multiple IV attempts, or because people are less careful about handwashing when the baby no longer has a central line, or (make up your own potential explanation and insert here).

I am not suggesting we back down on efforts to reduce central line infections; scrupulous attention to aseptic technique when handling a central line, full asepsis during insertion, enormous care around dressing cleanliness and maintenance, and so on are essential. But preventing translocation of intestinal bacteria, the real culprits in LOS, is going to give more benefit in terms of LOS.

How to do that? Infants with strong colonization of their GI tract with bifidobacteria and other probiotic organisms are at lower risk. And although there is some evidence that probiotic supplementation decreases LOS, the impact seems limited at present. Enhancing the efficacy of probiotics, by the addition of appropriate prebiotics, in particular the human milk oligosaccharides such as  2′-fucosyllactose, which feeds bifidobacteria, and is found in human milk, might really help to normalise gut colonization, which displaces pathogens and may reduce LOS.


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Progesterone doesn’t prevent prematurity?

Progesterone analogues, including 17-OH progesterone caproate have been investigated over the last several years for prevention of prematurity. In the pivotal trial from 2003 17OHPC intramuscularly once per week was shown to reduce prematurity at less than 37 weeks, less than 35 weeks (from 31% to 21%) and less than 32 weeks, and to reduce complications of prematurity (NEC and IVH).

Since then the literature has been a bit mixed, with many studies of different ways of administering progesterones being performed, many with daily vaginal pessaires, and some with oral administration, as well as others with the 17OHPC. Many studies among different groups at risk of prematurity have been positive (twins, short cervix, early cervical dilatation, premature rupture of membranes) but a few have been negative, and many small underpowered trials have appeared.

The newest trial was an attempt to reproduce the first Meis trial (Blackwell SC et al. 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial. American Journal of Perinatology. 2019).  An international RCT was performed with nearly 3 times the sample size of the previous study (n=1700), admission criteria were similar to Meis; that is a mother with a previous spontaneous preterm birth (with or without earlier rupture of membranes), and pregnant again with a singleton between 16 and 20 weeks of gestation.

Despite similar criteria for enrolment the actual placebo group rate of prematurity was much lower than Meis et al, at 11.5%. The intervention was identical, with 17OHPC weekly, and the outcome variables were also similar. The treatment group rate of prematurity < 35 weeks was practically identical to the controls, at 11.0%, that is there was no apparent treatment benefit.

Following this new trial an advisory committee of the FDA has recommended that the licence of 17OHPC be revoked in the USA. The submission of Public Citizen to that committee follows their tradition of brain-dead comments on pivotal perinatal trials. They state that the Meis trial was “seriously flawed”, but the only thing they note to support this statement is that an FDA statistician had stated that there wasn’t a second confirmatory study. No other “serious flaws” are described, and they quote the statistician as saying “The results of the analyses of the 32 and 35 week endpoints suggest their false positive rates could be as great as 1/40”, which is of course substantially better (p<0.025) than the 1/20 false positive rate that is usually required!

What about other trials? There are many systematic reviews covering various aspects of progesterone use. A network SR and meta-analysis was published this year (Jarde A, et al. Vaginal progesterone, oral progesterone, 17-OHPC, cerclage, and pessary for preventing preterm birth in at-risk singleton pregnancies: an updated systematic review and network meta-analysis. BJOG. 2019;126(5):556-67).

This was the result of the meta-analyses of delivery before 37 weeks. The earlier threshold chosen for this review was 34 weeks, and, for the 17OHPC, Meis reported prematurity <35 and <32 weeks, so the meta-analyses for delivery <34 weeks has very few patients, and doesn’t include Meis, it is basically just the Grobman trial which showed a small reduction with the drug.

As you can imagine the authors of the new trial were a little perplexed at the lack of effect, given the prior data. One of their suggestions is that, given the prior data regarding benefits of progesterones, many physicians were already prescribing them to the highest risk patients, and those who remained to be randomized had a much lower rate of premature delivery, which reduces power and perhaps selects a group with less progesterone responsiveness.

It remains a possibility of course that 17OHPC is not a very effective method of getting progesterones into mothers, and that the benefits shown in the Meis trial were indeed a “false positive”. Perhaps by chance they enrolled a control group which had a much higher rate of preterm delivery than the treated babies (which is a possibility but is unlikely), or perhaps there was some other bias in the study design, but I can’t see one.

Of course, it is also possible that the new trial is a false negative, the 95% compatibility intervals for the relative risk of preterm delivery before 35 weeks include the possibility that there is a 29% reduction (or indeed a 26% increase) in this outcome.

To keep this all in context of the entire literature about progesterones for preterm delivery, the comparative trials of vaginal progesterone and 17OHPC seem to show that the vaginal progestrone is the more effective of the 2, but includes numerous small trials and a couple of more moderately large trials, as you can see in the figure above. It is a treatment which has the advantage of avoiding weekly IM injections also. However, the confidence intervals are wide and only one individual trial showed a meaningful difference between the interventions, also the majority of the trials were unmasked, so the confidence in the advantage of vaginal progesterone is very low.

In fact if you critically look at the vaginal progesterone vs placebo trials it is only the smaller trials that show benefit, the 3 larger trials, Crowther, O’Brien and Hassan, don’t show very much.

I think the best way to settle this would be…. (drumroll…) another trial! I think that, in an ideal world (with very compliant mothers) we would perform a very large 3 arm trial with vaginal progesterone plus IM placebo, vs vaginal placebo plus IM 17OHPC, vs vaginal placebo plus IM placebo.

That won’t happen! So what could reasonably be done? I think it is probably inappropriate to take 17OHPC off the market; as well as the evidence of efficacy from one high quality trial with very high prematurity rates in both arms, there has been no real evidence of adverse secondary effects in any of the trials, including in long term baby follow up. Maybe this new trial will create enough uncertainty that a simpler trial than the one I suggested above could be performed, and try to enroll the highest risk mothers, but I am at a loss really.

The more I read about these trials, the more confused I get, and I end up being unconvinced by any of the data. The best 2 trials of all, I think, are Meis and the new Blackwell trial, and they come to different conclusions!

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Eye exams for fewer babies

In Canada, the current Canadian Pediatric Society recommendations, dating from 2016 are to screen infants for retinopathy of prematurity with Gestational Age <31 weeks or Birth weight <1,251 g.

These recommendations are already somewhat more restrictive than other countries, in the UK the limits are 32 weeks and 1500g, and in the USA <30 weeks or less than 1500 g, plus selected very unstable babies up to 2000g.

The larger and more mature infants are known to be at lower risk than less mature babies. The question that was asked in the study reported in this new publication was whether we really need to screen all those babies. Sabri K, et al. Refining evidence-based retinopathy of prematurity screening guidelines: The SCREENROP study. Paediatrics & child health. 2019.

In this study using data collected by our Canadian Neonatal Network the risks of developing significant RoP and of developing RoP requiring treatment were modelled using multiple different risk factors. There were nearly 5000 screened babies, and they divided RoP into type 1 or type 2 according to ETROP guidelines. Type 1 ROP is defined as
any stage 3 or plus disease in zone 1, or stage 3 and plus disease in zone 2 (and is considered to need urgent treatment). Type 2 ROP is defined as zone 1, stage 1 or 2 without plus disease or zone 2, stage 3 without plus (and is considered to need close follow up to detect progression). Any baby with type 1 or type 2 RoP, or who had detachment without treatment, was considered to be Clinically Significant RoP (CSROP).There were about 460 babies overall with CSROP, and 250 who had intra-ocular treatment with laser or VEGf inhibitors.

The cohort was split into 2/3, used to derive a model, and another 1/3 to validate the model.

In the end only birth weight and gestational age were required to develop a model which identified babies whose risk of CSROP was 1% or more. Using cutoffs of 1200 g birth weight or 30 weeks gestation identified all of the babies with RoP treatment, while screening fewer babies, and including all the babies except one with CSROP, a baby who did not need treatment. If these limits had been applied to this, development, cohort 20% fewer babies would have been screened.

Applying the model to the validation cohort confirmed the findings, and required 30% fewer babies to be screened, without missing any CSROP, except for a baby of over 1800g and over 32 weeks who was screened for specific individual reasons and did not fit the current screening guidelines anyway,

RoP screening is time consuming and the medications and procedure can cause significant instability in the babies. It also hurts (mostly, I think, because of the lid retractors) and analgesic interventions are only partly successful. Sometimes back-transport to level two centers is delayed, or the babies are re-transported back to tertiary centers for their eye exams. Most centers that I know in Canada have a very busy group of pediatric ophthalmologists, with at least intermittent difficulty in assuring timely exams.

For all these reasons, if we can reduce the number of eye exams by eliminating those with very low risk of developing clinically significant RoP, that is surely a good thing.

We have to keep in mind, that on an individual basis there is still the occasional extremely sick baby with prolonged instability who may need to be screened who was larger or more mature than these limits, but the large majority of babies who are over 30 weeks and over 1200 g could be eliminated from screening programs.

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Not futile any more; survival and long term outcomes at 22 weeks.

Imagine, if you will, that you work at a breast cancer center with moderately good results, but you have decided, as a group, to not offer therapy to women with stage 4- triple negative lesions. Survival is so low, you have decided, and the therapy so aggressive, that women should not be put through such a “futile” therapy.

But reports come in of other centers with survival well over 50%, long term outcomes which are excellent (as good as other types of breast cancer), and the short term complications of therapy which are similar to those of less aggressive cancer.

For the next woman who arrives in your center, what do you say? I think you would have 3 options:

1. “I know that in Superville they get good results, but they practice some sort of black magic: here in Ordinaryton we have decided that this is futile therapy so I am afraid you are going to have to die. We do have great palliative care though!”

2. “In Superville they are getting good results, so we are going to go ahead and do our thing too, let’s go!”

3. “In Superville they are better than us with other high-risk breast cancers also. We should gear up to offer therapy to women with triple negative cancers, let’s learn from Superville, and from the other centers who have also reported good results. Let’s make sure all of our team is up and ready. Let’s make sure we know how to do this the best we can. Let’s discuss each case individually with the patient, including all the details of the staging, and the risks of therapy and be ready to treat the next one who opts for intervention.”

It is fairly obvious what we should do to offer the best care (if transfer to Superville is not an option!) Just deciding that all such patients should die, while in several centers they can survive with a good quality of life, is not morally defensible.

Back to neonatology:

About a year ago I published a post talking about survival at 22 weeks gestation, a gestational age which is considered “pre-viable” by many practitioners, I noted that survival rates were high enough that “futility” could not be used as an argument against offering active support for such babies.

That post showed that several centers were achieving good survival at 22 weeks gestation. Total numbers of survivors were small, and very little follow up data was available.

The group in Iowa have just published detailed information regarding their outcomes, short and long term, over a 10 year period. Watkins PL, et al. Outcomes at 18 to 22 Months of Corrected Age for Infants Born at 22 to 25 Weeks of Gestation in a Center Practicing Active Management. J Pediatr. 2019. During that period active intervention was offerred whenever live birth at 22 weeks best-guess gestational age (BGGA), or more, was expected. The obstetricians offerred antenatal steroids and active surveillance. During that period there were 24 infants born alive at 22 weeks (I will concentrate on that subgroup, even though I know that intervention at 23 weeks is still not offered in many places. Some of the data are only available for the combined group of 22 and 23 weeks). Of those 24, 2 died before admission to the NICU, and 2 families opted for no resuscitation. None of the 22 week BGGA babies were delivered by Cesarean. This being from the USA, 7% of the mothers had no antenatal care prior to being admitted for threatened preterm delivery.

The obstetric team had time to give antenatal steroids to over 90% of the mothers, and half had more than 48 hours of coverage. Of the 20 babies admitted to the NICU, 14 survived to go home,  and the list of in-hospital morbidities and their frequencies for the 22 and 23 week babies together are similar to what you would expect for extremely immature babies, and are not noticeably different from the 24 and 25 week cohort, that they also report.

Survival to discharge is remarkably good for the overall 22-23 weeks cohort, as well as for the 24-25 weeks group, 78% and 89% respectively.

With regard to long term outcomes at 18 to 24 months corrected age, the majority of infants evaluated had no or mild “NDI”. In this study the Bayley 3 test was done, and if the cognitive score was over 85, and the child was free of CP (or had a GMFCS of 1), hearing or visual impairment, that was considered no or mild impairment. 70 to 84 on the cognitive scale, or CP with a GMFCS of 2 or 3, was considered moderate impairment, and lower scores or worse CP was considered severe. 82% of the 22 week group were no, mild, or moderate, “NDI”, with 2 of the 11 evaluated survivors having severe NDI. The proportions between the different weeks of BGGA are similar, but do look a bit worse at 22 weeks, the numbers are small to evaluate statistically, however.

As you might realize if you have seen Annie Janvier’s recent contribution to John Lantos’ ethics rounds series in Pediatrics. (Janvier A, et al. Does It Matter if This Baby Is 22 or 23 Weeks? Pediatrics. 2019). We have offered active intervention to several babies at 22 weeks BGGA at our center, with a few hiccups during the hospital course of the first one, which you can read about in those rounds, but there has been a gradual acceptance in the NICU that survival and outcomes are good enough to offer NICU care.

Starting to do this, and getting good enough at it that you can get good survival (both numbers and quality), requires an integrated approach with Obstetrics. Offering NICU care if the obstetricians are not prepared to give steroids, is not a reasonable approach and will not likely be successful. No center is going to have many such babies, even in Iowa they only average 2 per year at 22 weeks, so having pre-existing protocols and a joint approach, all ready for the next mother who arrives is essential. If your obstetricians are reluctant to give steroids, you can show them this figure from (Travers CP, et al. Exposure to any antenatal corticosteroids and outcomes in preterm infants by gestational age: prospective cohort study. BMJ. 2017;356:j1039).

This is a graph of the number needed to treat per extra survivor, according to GA at birth. Data are from the Pediatrix data warehouse, and the total n is about 120,000.

At 23 weeks you only need to give 8 courses of steroids per extra survivor, compared to almost 1000 at 34 weeks! That study collected no data at 22 weeks gestation, but I can’t see any reason why the curve, which seems to flatten off a bit at the bottom, would suddenly leap upwards again.

In addition to the collaboration with obstetrics, consistency of the clinical approach, and a positive attitude seem to be essential. Having visited both Iowa and Uppsala recently, I can tell you that those 2 centers clinical approaches have multiple differences. Incubator care, ventilation, blood work, just about everything, seems different. The most important factor that they seem to have in common is that the people looking after the most immature babies believe in what they are doing, talk together frequently about how to improve their care, and expect that the large majority of the 22 and 23 week babies will survive. That has to include the entire team, from nurses to admission clerks to respiratory therapists (if you are lucky enough to be in a country with RTs), and of course integrating the parents.

I don’t think it is morally defensible to just tell parents ‘we don’t do that here’, and particularly not ‘it is futile’. Decision-making based on individual risk assessment, with a realistic option of high-quality committed active care should be offered.

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How fast to feed?

One of the recurring themes in this blog is that good, large enough, prospective RCTs do not necessarily reproduce the results of prior smaller trials, and often do not reproduce the findings of observational studies. Specifically, I have mentioned previously that observational studies suggesting that slow feeding advancement leads to less Enterocolitis in extremely preterm babies (NEC) than faster advancement have never been confirmed by prospective trials.

There were several trials of feeding advancement, of variable quality and relatively small sample sizes, before 2016, which showed no overall adverse impact of advancing feeds more quickly, but with sufficient uncertainty that a large simple pragmatic trial was warranted to address the question. The short term results of the SIFT trial have been presented and incorporated into the Cochrane review Oddie SJ, et al. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane database of systematic reviews (Online). 2017;8:CD001241.

Those results showed no benefit of advancing feeds more slowly (18 mL/kg/day) compared to more quickly (30 mL/kg/day) among nearly 3000 infants of less than 32 weeks, or less than 1500g birth weight. The findings incorporated into the Cochrane review include secondary outcome data on NEC and infections.

The primary outcome of the SIFT trial was survival without neurodevelopmental disability to 24 months corrected age.  In the latest FPNEJM the primary and the secondary short term outcomes are now presented in full. Dorling J, et al. Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants. New Engl J Med 2019;381(15):1434-43. 2800 infants were randomized when receiving less than 30 mL/kg/day and the intervention started when ‘the clinicians were ready to start increasing feeds’ which occurred at a median of 4 days of age. The more rapid increase group reached ‘full feeds’ which was defined as 3 days of receiving at least 145 mL/kg/d, after a median of 7 days, compared to 10 days in the slower group. I don’t understand this entirely; if the baby was on 10 mL/kg/d and tolerated all the feed increments, it would take 5 days to get to at least 145 mL/kg/d and then another 3 days would be needed before satisfying full feeds criteria, which takes us to 8 days minimum. Anyhow, this is a minor quibble, on average the babies in the slow advancement group  had 2 days longer with intravenous nutrition. I can’t see in the publication any definition of feeding intolerance, or if there were any attempted standardization of feeding approaches to decide whether to continue advancing feeds.I beleieve the investigators decided to leave most details of feeding approaches untouched, only mandating the attempted feeding volume changes, and counting on a very large sample size even out everything else.

NEC was very slightly less frequent with faster feeds (5% vs 5.8%, RR=0.90, compatability intervals 0.66, 1.24) and late onset sepsis or clinical sepsis were very slightly less frequent also (30 vs 31%, RR=0.96, compatability intervals 0.85 to 1.08).

The differences between groups in the primary outcome also were tiny, survival was 95% in each group and so-called disability was 31% fast, vs 28% slow. Survival without ‘disability’ was 66% for the fast feeders and 68% for the slow. I won’t go into the details of how the outcome assessments were performed, most were by parent report, others by direct observation and evaluation.

In subgroup analyses published in the on-line supplement, there is no clear evidence of a difference in NEC or of nosocomial infections by gestational age subgroup. Infants with reversed or absent end-diastolic flow on antenatal doppler ultrasound of the umbilical artery also had no clear difference (although in this subgroup faster feeding advancement had rather less NEC, 3.8 vs 7.1%, this may have been due to chance effects in this subgroup (435 babies) and the interaction term was compatible with a chance effect).

In the Cochrane review mentioned above data on ‘invasive infections’ are presented, which refers to culture-positive infections. The number of infants with at least one invasive infection was 247/1389 vs 267/1397 in the SIFT data included in that review (I can’t find those data in the new publication) that gives a relative risk, favoring faster feeds, of 1.07 (compatibility limits 0.92, 1.96) when the data from the other 600 babies included in all the other trials is added, the RR is 1.15 (95% limits 1.00, 1.32). Similarly the data from all trials in the meta-analysis, including SIFT data, show a slightly higher rate of NEC with slow feeding RR=1.07, 95% compatability intervals 0.83, 1.39).

SIFT is consistent with the previous trials, but gives enormously more precision to the estimates, it shows that feeding faster, up to a goal of 30 mL/kg/ has no adverse impact overall, or in any subgroup, compared to feeding slower (goal of 18 mL/kg/d). Even though the babies had a median of 2 days less of parenteral nutrition that did not lead to a clear reduction in proven and suspected infections, there seems to be a small reduction if all the available RCT data are analyzed.

Of note, the late-onset sepsis rates appear to be extremely high; 540 of the 889 babies under 28 weeks had a suspected or proven infection, or 61%. But of course that includes ‘suspected infection’ which basically means anyone with any sort of clinical deterioration that is treated with antibiotics for more than 48 hours. If I compare the total numbers of proven and suspected infections in the final publication (848) to the culture positive infections in the Cochrane review (514), then about 60% of their LOS is culture positive. If the same proportions hold in smaller gestation age groups, then about 36% of babies under 28 weeks had a culture positive sepsis. That approaches the kind of incidence of culture positive infections in other multicenter databases, but remains somewhat high. In the 2017 CNN report, for example, adding together the <25 weeks and the 25 and 26 week gestation babies ((i.e. the higher risk infants, excluding those at 27 completed weeks) the proportion with at least one infection, culture positive, is 28%.

The trial was powered to have a reasonable chance of showing a difference in sepsis, based on the assumption that 1000 fewer catheter-person days per 250 infants would lead to fewer infections. In fact there were about 500 fewer parenteral nutrition days (I can’t find the data for catheter-person days) per 250 enrolled infants, or about 5000 fewer days overall, which didn’t seem to have any measurable effect on infections. Even when looking at culture positive infections alone, there was really nothing there. There are a number of potential explanations for this. As I have mentioned before, the emphasis on catheter linked sepsis is excessive in the preterm infant. Many LOS are caused by enteric gram negative pathogens, and reducing CLABSI doesn’t necessarily lead to a reduction in overall sepsis, by a logical extension, reducing catheter duration may reduce CLABSI but without reducing overall infection rates. On the other hand the CLABSI rate per 1000 patients days is lower in the first week of catheter use compared to later, and the median 2 days of increased duration of parenteral nutrition may not have exposed the babies to much difference in risk. Sanderson E, et al. Dwell time and risk of central-line-associated bloodstream infection in neonates. J Hosp Infect. 2017;97(3):267-74.

What next? I think that a trial comparing the fast feeding approach in this study could be compared with an earlier start of advancement at a slightly greater rate. The comparison approach could be to enrol babies on day 1, start feeds immediately at 2 mL/kg q2h, and start advancement immediately at say 40 mL/kg/d. In my practice we now usually start feed advancement before 4 days of age, and, if the infant is not in shock, advancement starting day 1 would be just fine by me. We would have to use temporarily a bit more donor breast milk (PDHM), which could be a downside to advancing sooner. An earlier start to advancement might lead to a greater difference in catheter and parenteral nutrition duration, and, potentially, a subsequent impact on sepsis. Perhaps we might find less CLABSI, but no less systemic infection.

So far there is no good quality prospective controlled data that any approach to starting or advancing feeds has any impact on NEC.

The evidence-based strategies to reduce NEC are to promote and support MOM (mother’s own milk), have PDHM available when MOM is insufficient, to have a standardized feeding protocol, and to use a probiotic preparation with good quality control, which contains bifidobacteria and probably a lactobacillus or a streptococcus.

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