Anti-reflux medications in preterm infants; a whole cornucopia of toxic placebos.

Posted on 2 December 2016 by Keith Barrington

I have written frequently about this on my blog in the past, and even written a book chapter about the subject (in the book titled “Nutrition for the Preterm Neonate” edited by Sanjay Patole). I recently mentioned the subject in my comments on the AAP choosing wisely recommendations.

The reason for posting about this now is a new publication, from a multi-site network of pediatric primary care practitioners that indicates that 37% of the babies born before 36 weeks received medication for reflux in their first year of life, most of which was started after NICU discharge. (D’Agostino JA, et al. Use of Gastroesophageal Reflux Medications in Premature Infants After NICU Discharge. Pediatrics. 2016). 40% of the treated babies received 2 medications, usually simultaneously, very often the 2 medications were both acid blockers, and some poor babies were getting 3 different acid blockers.

If you click on Gastro-oesophageal reflux in the word cloud at the left of this post you will be taken to a series of posts that address the issues.

But I will summarize:

Almost all babies have reflux, and almost all regurgitate occasionally, so we need to define what is GERD (GORD in England and anywhere else they know how to spell properly) or gastro-(o)esophageal reflux disease:
that is actually more difficult than you might expect, but basically that term means disease caused by gastro-oesophageal reflux, and includes changes caused by intestinal contents refluxing into the oesophagus or higher. Many articles about GER have diagnosed reflux by a percentage of time with acid in the oesophagus that is more than the 90th -percentile, which of course would mean that 10% of babies have ‘pathological’ reflux. But does that identify those babies that have reflux disease? Clearly not.

Can we clinically diagnose reflux? Basically no.

In the NICU there are no clinical signs which have been shown to differentiate between babies that have “excessive” reflux and those without, and one study with pH metry and video monitoring found just as many “reflux specific” clinical signs when the infant was not refluxing as when they were. Another study found that there was no correlation in the scores on 2 different supposedly validated scoring schemes for reflux, and another study showed that anti-acid medications had no impact on the symptoms that were attributed to reflux.

There are of course 2 broad categories of agents that are used for reflux, those which are given to reduce the frequency or duration of reflux events, and those which are given to inhibit acid production and hopefully reduce the adverse effects of reflux.

The first category consists of metoclopramide, cisapride, domperidone and erythromycin, (apparently now there are even people using bethanechol). All of these agents are toxic placebos, or toxic and worse than placebo, (that is both metoclopramide and domperidone have been shown to increase reflux) as you will see from the blog posts about each of them. Indeed as these are all prokinetic agents (although cisapride may not be prokinetic in the newborn) it is not too surprising that they may not improve, or may actually worsen reflux; increasing stomach emptying can easily send the contents in both directions!

Suppressing acid production is neither effective nor safe. It does not decrease symptoms that are attributed to reflux, and is associated with multiple complications. This is true whether you use good old ranitidine, or the latest expensive PPI.

I don’t understand why pediatricians would treat so many ex-preterm infants with agents that are ineffective and have secondary effects. Their use in the NICU has I think been decreasing, but much care of former preterm infants may well be delivered by general pediatricians who do not have the same approach as we do.

Time for more education, and perhaps more regulation, of drugs that have not been adequately tested in this population, are of uncertain efficacy, and have important secondary effects.

In the meantime, if you have a baby where you are convinced that their symptoms are caused by acid reflux, and you can’t stop yourself from prescribing an acid-blocking drug, the least worst harm you could do would be perhaps a “therapeutic trial”. Which means that after a few days if there is no improvement, stop the therapy. If there is an improvement, you should also stop the therapy, to see if the change is just due to the baby getting older, and if the symptoms recur, then you have a reasonable indication for continuing the treatment.

Posted in Neonatal Research | Tagged | 1 Comment

Neonatal Sepsis after Chorioamnionitis, what to do about healthy appearing newborns

Posted on 23 November 2016 by Keith Barrington

In 2007, when I was chair of the CPS Fetus and Newborn Committee, we published a guideline regarding the approach to term and late preterm infants with perinatal risk factors for sepsis. Obviously any infant with clinical signs consistent with sepsis needs immediate work up and antibiotics, but the management of infants with risk factors for sepsis and no clinical signs evident was the focus of that guideline.

This is what we said about chorioamnionitis, based on what we thought was the most reliable literature:

The risk of sepsis (which may be due to a variety of different organisms, including GBS, E coli and other Gram-negative organisms) in an infant whose mother had definite chorioamnionitis is approximately 8%, and is approximately 3% to 4% if ‘possible’ and ‘definite’ chorioamnionitis are considered together [31][32] (evidence level 2b); among all mothers with fever, the incidence is 2% to 6% depending on the height of the fever [31] (evidence level 2b). Infants who do not have signs at birth are unlikely to develop sepsis, the odds ratio for sepsis among infants who are well at birth is 0.26 (95% CI 0.11 to 0.63) [31]. The incidence of invasive infection in the present study in an initially well-appearing infant with a maternal history of fever or chorioamnionitis was less than 2%, and this is confirmed by other data [33] (evidence level 2b). Therefore, it seems reasonable to perform a CBC and closely observe such an infant, and to only perform a full diagnostic evaluation and treat with antibiotics if the CBC is strongly suggestive of infection (low total WBC count) or if clinical signs develop. A requirement for extensive resuscitation at birth should be considered a sign of possible infection in such infants [32][33].

At that time the CDC guidelines recommended cultures and empiric antibiotics for all such infants, the CDC guidelines were updated in 2010, and continue to recommend the same thing, with the clarification that you should talk to the obstetricians (always a good idea!)

Well-appearing newborns whose mothers had suspected chorioamnionitis should undergo a limited evaluation and receive antibiotic therapy pending culture results (AII). The evaluation should include a blood culture and a CBC including white blood cell differential and platelet count; no chest radiograph or lumbar puncture is needed. Consultation with obstetric providers to assess whether chorioamnionitis was suspected is important to determine neonatal management (CIII).

Is there anything new recently? I think you all know the answer to that question.

Braun D, et al. Low Rate of Perinatal Sepsis in Term Infants of Mothers with Chorioamnionitis. Amer J Perinatol. 2016;33(02):143-50. This database analysis from Kaiser Permanent Southern California found an incidence of maternal fever in labour (38 degrees or more) at or after 35 weeks to be 9% and chorioamnionitis (based on ICD-9 codes from discharge data) to be 4%, chorioamnionitis based on a fever of 38 degrees followed by antibiotic treatment was 5%. There were around 30,000 deliveries in this cohort and in total there were 19 babies with culture positive early onset sepsis, 14 were symptomatic and 5 had bacteremia without clinical signs. That gives an overall incidence of culture positive symptomatic sepsis of 0.45 per 1000, and of culture positive bacteremia without clinical signs of 0.16 per 1000. Among mothers without fever the rate of sepsis was 0.5 per 1000, if they had fever without chorioamnionitis it was 0.6 per 1000, and if they had chorioamnionitis it was 4 per 1000.

One interesting thing in this study is that many physicians do not follow the CDC guidelines, the rate of neonatal treatment with antibiotics after maternal chorio, which should be close to 100%, ranged from 7 to 76% in different hospitals.

The authors don’t say how many of the babies without clinical signs were from the maternal chorio group, there were 5 babies who did not have clinical signs, if all of them were from mothers with chorioamnionitis (which I think is unlikely) then you would have to treat 250 clinically well infants after maternal chorioamnionitis with antibiotics to be sure to cover 1 baby with bacteremia. Of course if some of those babies were symptomatic, then you would have to treat many more without clinical signs for each baby infected, for example if the proportion of asymptomatic babies is the same as in the next study (about 1/3) then you would have to treat over 700 asymptomatic babies to cover that 1 with bacteremia.

The authors also calculated that if the CDC guidelines had been followed (for chorioamnionitis, but also for other indications for neonatal antibiotic treatment) then 8% of all the term and late preterm babies would have received 48 hours of antibiotics.

Another very large study Wortham JM, et al. Chorioamnionitis and Culture-Confirmed, Early-Onset Neonatal Infections. Pediatrics. 2016;137(1). instituted prospective surveillance for early onset sepsis among nearly 400,000 deliveries. In contrast to the other study they did not collect data from mothers whose babies did not get septic, so we don’t know overall incidence of chorioamnionitis in this study, and you can’t make some of the same calculations.
They found 389 cases of early onset, culture positive, infections, in the cohort which included both preterm and term babies. Eighty-one of those infections were in term babies (37 weeks and more; from 350,000 term deliveries) 58 of which had clinical signs at birth. Which leaves 23 term infants who had no signs at birth but had culture positive sepsis, from mothers with chorioamnionitis, and 6 preterm babies with the same combination. The authors include some babies, 1 at  term and 4 preterm, who only had histological evidence of chorioamnionitis, which doesn’t help our decision-making as you don’t know about those unless you did placental pathology and got the results back.

If the prevalence of chorioamnionitis is 4 to 5% (as in the first study), then there would have been about 16,000 cases of chorio among the term deliveries, which gives the incidence of early neonatal sepsis (81/16,000) of 5 per 1000 which is very similar to the Kaiser Permanent data. We know 23 were without signs at birth (but one of those would not have had a diagnosis of chorio) so to ensure that 22 those asymptomatic babies with sepsis received early treatment, you would have to screen, culture and treat 16,000 babies, which is a number needed to treat of over 700.

I think that is too many. NICE in the UK seems to have a similar opinion in their guideline from 2012, their guidance is a little more complicated, but goes like this (the links should work to take you to the tables):

Use the following framework based on risk factors and clinical indicators, including red flags (see tables 1 and 2), to direct antibiotic management decisions:

  • In babies with any red flags, or with two or more ‘non-red flag’ risk factors or clinical indicators (see tables 1 and 2), perform investigations (see recommendations 1.5.1.1–1.5.1.3) and start antibiotic treatment. Do not delay starting antibiotics pending the test results (see recommendations 1.6.1.1–1.6.1.3).
  • In babies without red flags and only one risk factor or one clinical indicator, using clinical judgement, consider:
    • whether it is safe to withhold antibiotics, and
    • whether it is necessary to monitor the baby’s vital signs and clinical condition – if monitoring is required continue it for at least 12 hours (at 0, 1 and 2 hours and then 2-hourly for 10 hours).

     

In their scheme chorioamnionitis is a risk factor, but not a “red flag”, so if the baby does not have any of the clinical indicators they would be observed, but not treated.

As I said I think that an NNT of over 700 is too many, but others may not agree, specifically the parents may not agree. Shouldn’t they be involved in that decision? A decision aid may help them to decide, with the medical team, between one or multiple IV installations, antibiotics for 36 hours (you can stop them before the 48 hour dose if cultures are negative) and hospitalisation for at least that long. Depending on how your hospital is organized term newborns on antibiotics may also not be in the room with the mother. The contrasting choice is close observation with the option of starting antibiotics later if clinical signs appear (which happened in 18 of the 23 initially asymptomatic term babies with positive cultures). Also there is no difference in mortality (there was one death in the Wortham study, a baby who died soon after cultures and never had antibiotics, 2 deaths in the Braun study both of whom were symptomatic) shown in these recent studies.

Very frequent use of antibiotics of course affects colonization and resistance patterns in an environment, and will affect the development of the infant’s microbiome, perhaps for many months or years.

I think in these days of shared decision-making and family centered care, when a term baby is born after maternal chorioamnionitis but is clinically well, we should inform the parents that the baby has a very small risk of having an infection, (1 in several hundreds) and that there are 2 options. We should also organize our care so that both close repeated observation, and/or antibiotic administration, can be performed in a mother and infant room, without interfering with breastfeeding and the evolution of the new family, and then give the parents a big place in that decision.

 

Posted in Clinical Practice Guidelines, Neonatal Research | Tagged , , | 1 Comment

Podcast starring Annie Janvier: the harms of a gestational age label

Posted on 22 November 2016 by Keith Barrington

The Archives of Disease in Childhood (and several other BMJ journals) have a series of podcasts, most of them seem to be interviews between a member of the editorial board and an author of a recent article. In this new one Jonathan Davis, one of the associate editors of the fetal and neonatal edition, interviews Annie Janvier about an editorial that she has just written for the journal. (Delivery room practices for extremely preterm infants: the harms of the gestational age label)

I already posted about the associated article and mentioned the editorial, but the podcast is 24 minutes long and goes into more detail about some of the issues.

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Maternal complications of extremely preterm delivery

Posted on 22 November 2016 by Keith Barrington

When there is a threatened delivery in the periviable period, one of the decisions that have to be made is about the mode of delivery. In my opinion (IMHO, I think those young’uns say) we should consider the different parts of the decision-making to be linked but separate. A decision to give antenatal steroids, for example, does not mandate a cesarean delivery or intensive care of the baby. A decision to not perform a cesarean does not mean that fetal heart rate monitoring should not be performed, or that a live-born baby might not have active resuscitation.

One might decide, for example, that a mother will receive betamethasone, with a goal of improving the chances of a good outcome, and we might then decide to plan on providing active intensive care for the baby, but then the decision may be that the risks and benefits, for this particular mother, of performing a cesarean are not consistent with her goals and values; in which case a cesarean for fetal indications will not be performed. We might still want to monitor the fetal heart rate, as knowledge of the heart rate during the last minutes prior to delivery could help in resuscitation decisions; if the fetus has been bradycardic for a prolonged period prior to delivery, and is then born asystolic, a decision to not attempt resuscitation could be quite reasonable, compared to a fetus with good heart rate patterns just before delivery.

One part of this decision-making matrix that has been somewhat lacking is good data about maternal complication rates in this time period. What are the risks to the mother of a classical cesarean, a lower segment cesarean, or a vaginal delivery before 26 weeks? What are the risks for this pregnancy, and for the next pregnancy?

Several recent articles, one still on-line only, help to clarify the risks (although the relative benefits of each mode of delivery need RCTs for reliable scientific data, which may well never be done).

These articles are all therefore observational studies, which describe the frequency of various maternal outcomes after preterm delivery.

The first article answers a question for which I last did a literature search a couple of years ago, at that time I wasn’t able to find any good data, : “what is the risk of a classical, or an extremely preterm lower transverse, cesarean on uterine rupture in future pregnancies?” This risk is often stated by obstetricians to be a major part of their reluctance to perform a cesarean in the periviable period, and although the risks are clearly greater than for a vaginal delivery I was never sure what was the magnitude of that risk. In this publication the authors state that they also could find no good data, so my lit review was not inadequate, there just was no data. Their study, in contrast, gives very clear information about those risks.

Lannon SM, et al. Uterine rupture risk after periviable cesarean delivery. Obstetrics and gynecology. 2015;125(5):1095-100.

The authors used linked databases from Washington state to determine the risks of uterine rupture in a subsequent pregnancy after a cesarean delivery performed at 20-26 weeks gestation, and compared the risks to a cesarean performed at term.

Overall, the risks of future uterine rupture after a periviable cesarean were about 1.8% (2.4% if you restrict the analysis to classical scars) compared to 0.4% after a cesarean at term. The results are also presented as an Odds Ratio (which is 4.9, 95% CI 1.7-13.1); unfortunately few physicians understand what an Odds Ratio is (but when the risks are small there isn’t much difference between the Odds Ratio and the Relative Risk). I think for individual mothers making a decision, that the absolute risks are more useful numbers; also a comparison to cesarean deliveries performed at term is an interesting and useful comparison to put the risks in context, but doesn’t help in decision-making much as that isn’t the option that would be on the table.

There is also a comparison of other maternal morbidities in the current (or “index”) pregnancy; periviable cesarean deliveries are a little more morbid (14% of mothers have one or more of transfusion, bleeding, coagulopathy, chorioamnionitis, sepsis, maternal infection or hysterectomy as recorded in the hospital discharge diagnoses, which means that bleeding is not strictly defined) than term cesareans, which I was a bit surprised to see were also pretty morbid (10% had the same complications) but the difference was consistent with a chance finding.

Mothers who have a periviable cesarean are different in many ways from mothers having a term cesarean, so how much of the increase in maternal morbidity is due to the classical incision (almost all of the term cesareans are lower segment transverse incisions) and how much to their other demographic and clinical differences? Also important, does having a cesarean delivery at periviable gestation have other effects on subsequent pregnancies, other than the risk of uterine rupture?

The same group (Lannon S, et al. Mode of delivery at periviable gestational ages: impact on subsequent reproductive outcomes. Journal of perinatal medicine 2013. p. 691.)
has looked at the risks for a subsequent pregnancy,  and compared a vaginal birth in the periviable period to a cesarean delivery. Overall having a delivery in the periviable period led to the same outcomes in a subsequent pregnancy regardless of mode of delivery, the gestational age at birth of the subsequent pregnancy were almost identical; the only individual outcome which was affected was uterine rupture. There were some very small differences, which were statistically significant because of the large numbers of pregnancies being evaluated, for example after a periviable vaginal delivery the median gestational age of the subsequent pregnancy was 38 weeks, and after a cesarean it was 37 weeks. the authors interpret this difference as the wish to perform cesarean in the subsequent pregnancy prior to labour to avoid uterine rupture if possible.

The next study compared the maternal outcomes of classical cesarean to low transverse cesarean on maternal morbidity (for the index pregnancy only). Kawakita T, et al. Maternal Outcomes associated with early preterm cesarean delivery. Am J Obstet Gynecol. 2016. They looked at hospital records of mothers who delivered between 23 and 32 weeks gestation, and then looked at the stratum under 28 weeks. They showed that in the higher gestational age stratum (28 to 32 weeks) that classical cesareans had more morbidity, in particular more transfusion and more need for ICU admission. But in the lower GA group the risks were the same for both types of cesarean incision, for example about 10% needed a blood transfusion in each group.

Another paper from the NIH MFM network examined deliveries between 23 weeks and 34 weeks.  Reddy UM, et al. Serious maternal complications after early preterm delivery (24-33 weeks’ gestation). Am J Obstet Gynecol. 2015;213(4):538 e1-9. Deliveries at 23 to 27 weeks gestation were more morbid, with 7% having hemorrhage, compared to 3% for the group at 31 to 33 weeks, in this study hemorrhage was clearly defined, as it was part of the prospective data collection, as blood loss ≥1500 mL, blood transfusion, or hysterectomy for hemorrhage.

The absolute risks associated with an extremely preterm cesarean delivery are not noted in this publication, but the adjusted relative risk of a cesarean delivery at 23 to 27 weeks compared to a vaginal delivery is presented. The combined relative risk of hemorrhage, postpartum infection, and ICU admission is 3.22 for a classical cesarean delivery and it is 2.8 for a low segment delivery, both compared to vaginal delivery at the same gestational age.

I can’t tell you based on these data what are the absolute risks, but I guess-timate from these data (about half of the deliveries were vaginal) that about 6% of mothers delivering vaginally between 23 and 27 weeks will have a serious complication, (hemorrhage infection or ICU) and about 18% of mothers who had a cesarean in this time interval. That is a bit higher than Kawakita if I have estimated the absolute risks correctly, but not too much different, and of course definitions and data finding are different.

Another study from the Canadian Perinatal Network (Crane J, et al. Maternal and Perinatal Outcomes of Pregnancies Delivered at 23 Weeks’ Gestation. JOGC 2015;37(3):214-24.)  included only deliveries at 23 weeks, serious maternal outcomes were common (about 40% of mothers had at least one serious outcome), but the large majority of them were chorioamnionitis, about 38%; after that the next most common was blood transfusion which was required in about 4% of women. About 10% of the 230-ish mothers had a cesarean, and the authors don’t compare the maternal outcomes between Cesarean and vaginal deliveries, but most of the data are from the vaginal deliveries.

To summarize, having babies is dangerous. Having a baby by cesarean section at term has risks, including a frequent need for transfusion. The overall risks of having a cesarean delivery in the periviable period for the current pregnancy are somewhat greater than at term, but the magnitude of the increase is probably less than 5%, most of those risks are short-term and treatable, with the most common being the need for a transfusion. A vaginal delivery in the periviable period has fewer risks for the mother  Uterine rupture in the next pregnancy, if there is one, occurs less than 3% of the time.

I want to emphasize here that uterine rupture is a big deal. I am not trying to minimize it, and we should find a way to explain to mothers the importance of uterine rupture in future pregnancies, but we should do that without exaggerating its incidence (perhaps a visual decision aid?), and ensuring that mothers understand the major impact of a uterine rupture, and that the risk of rupture persists even when the obstetrician tries to take steps to avoid it. Of course that is a risk which is important for a woman who will have a future pregnancy, and may be of little importance for a woman who has decided against that option.

I think that it is good for the neonatal team to have an understanding of the risks to the mother, so that we can be reasonable and well-informed as we participate in decision-making; but clearly the final decision about route of delivery should be made between the mother and her obstetrician.

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Breast milk doesn’t make you smarter?

Posted on 16 November 2016 by Keith Barrington

A newly published RCT seems at first glance to challenge the overall verdict of the literature that consuming breast milk improves intellectual development, particularly for preterm infants. (O’Connor DL, et al. Effect of Supplemental Donor Human Milk Compared With Preterm Formula on Neurodevelopment of Very Low-Birth-Weight Infants at 18 Months: A Randomized Clinical Trial. JAMA. 2016;316(18):1897-905).

180 infants were randomized to receive preterm formula whenever there was insufficient maternal breast milk. The other group of 180 received pasteurized donor breast milk whenever there was not enough breast milk. Infants received their assigned supplement until 90 days or discharge, whichever occurred first, and continued to get the assigned diet if they were back-transferred to a level 2 nursery before going home.

The study was well-designed and carried out, but unfortunately vastly underpowered. All NICUs now try and give mother’s milk to the babies, which is always the first choice, so nearly 30% of the babies in each group never received a supplement, which makes them uninformative for the primary outcome, which was Bayley Testing at 18 months of age.

Of those that did receive a supplement, the median proportion of total enteral feeds for each infant consumed as mother’s milk  was 58.4% [IQR, 13.6%-96.0%]  for the donor milk group vs 63.3% [IQR, 9.6%-97.2%] for the formula group. So in other words some of the babies received as little as 3% of their feeds as the assigned diet, and about half received around 40% or more.

I think its fairly obvious that receiving only a tiny proportion of your feeds as formula is highly unlikely to have a measurable effect on developmental delay. The only babies that you might think could possibly have an effect would be those with a significant percentage of their milk being donor milk, rather than formula.

As you can see from those figures above, half of those who did get the assigned diet received more than 40% of their feeds as something other than mother’s milk. We could guess that 40% might be enough to show an effect if there was one, if we use that as the threshold, there were only approximately 60 babies per group, of whom 92% had follow up, or about 55. The power of detecting an effect on development with only 55 per group is rather low.

I understand the need to do intention to treat analysis, but in a study such as this, where it was expected that 30% of the babies would never receive the assigned intervention, (and not because of protocol deviations, but because the mother is able to produce enough milk) you could easily argue that the main analysis should be among those who did actually need a supplement.

This is not the same as, for example a study comparing planned vaginal breech delivery to planned cesarean, where the clinical question is “what should I plan for the delivery of this baby?” The clinical question here was, “if we need to supplement, what should we do it with?” and it is a question that can be posed when you get to the point of there not being enough breast milk. Enrolling mothers and getting consent could be done soon after birth, but actually randomizing and collecting data could be done only when the baby needs a supplement, which would increase the power of the study.

As it is, there are a limited number of babies in the trial who are informative for the outcome, which means that a substantial benefit (or harm) of supplementation with donor milk, on the primary outcome, could have been missed.

Secondary outcomes are also underpowered, but even with this lack of power, there was a significant reduction in NEC, from 6.6% (stage 2 or more) with formula supplementation to 1.7%, with donor milk as a supplement. Other outcomes including late onset sepsis were not different between groups.

There are all sorts of goodies in human milk for preterm babies, and this study confirms that NEC is less frequent when you supplement with donor milk compared to preterm formula. It wouldn’t be surprising that the impact on NEC required less cow’s milk than an impact on developmental delay, so a large relative difference between groups, for this outcome, is biologically plausible.

Also of note, most of the babies in this study were exposed to cow’s milk protein. Both in the formula group, but also in the breast milk groups, as milk was fortified with cow’s milk based breast milk fortifier, even if the baby only received their own mother’s milk.

The conclusions state the following:

Results from the present study suggest no advantage of feeding nutrient-enriched donor milk compared with preterm formula, as a supplement to mother’s milk, on neurodevelopment of VLBW infants at 18 months’ corrected age.

But that isn’t quite right, the study suggests no advantage of a strategy of being ready to receive nutrient enriched donor milk if needed, compared to a strategy of getting formula if needed. That comparison showed no overall impact on Bayley scores, but did show a benefit in terms of NEC.

The results are consistent with a substantial effect of breast milk on neuro-development, (as well as being consistent with no effect or with a negative effect).

To be honest, I don’t think we need to do more studies like this, concentrating on helping mothers to express their milk, and when necessary supplementing with donor milk, should be the standard of care. This study confirms the benefits in terms of NEC, and didn’t show any downside of breast milk supply to preterm babies.

Posted in Neonatal Research | 3 Comments

Teaching clinicians to evaluate encephalopathy

Posted on 10 November 2016 by Keith Barrington

I hope this link stays active for ever as it is a great resource… Courtney Wusthoff from Stanford has developed a web-based educational tool, designed initially, I think, for medical (pediatric) residents. Their team has evaluated whether or not this works by showing pediatric residents videos of actual examinations of asphyxiated newborn infants, and asking them to identify whether the babies were normal or had encephalopathy that was either mild moderate or severe. They repeated the process after using the web-based tool described above.

They showed substantial improvements in the skills of residents in evaluation of such infants. Ivy AS, et al. Improving the Identification of Neonatal Encephalopathy: Utility of a Web-Based Video Tool. American journal of perinatology. 2016.

Hey, the internet works, sometimes!

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38 weeks is too early

Posted on 10 November 2016 by Keith Barrington

In New South Wales (the part of Australia around Sydney) their public health databases record not just gestational age, but the mode of delivery and whether there was an induction of labour, or labour prior to caesarean delivery. In the same part of Australia, every 3 years, during their first year of full-time schooling, children are evaluated by their teachers using a validated tool called the AEDC, which stands for Australian Early Development Census. This tool evaluates development in 5 domains: physical health and well-being, language and cognitive skills, social competence, emotional maturity, and communication skills and general knowledge.These data are also entered into a database.

Just imagine what you could do if you put the 2 databases side by side!

Well, you could do something amazing like this: Bentley JP, et al. Planned Birth Before 39 Weeks and Child Development: A Population-Based Study. Pediatrics. 2016. You could look at early term, and late preterm deliveries, and find out if having a labour induction at 37 or 38 weeks was safe, in terms of developmental outcomes.

You would have to decide what you considered to be an adverse outcome: such as being below the 10th percentile for 2 of the AEDC domains, which you would then call “developmental high risk” or DHR. This was indeed the primary outcome variable for this study, that looked at gestational age in completed weeks from 32 weeks onward, and mode of, and indication for, delivery. The authors were able to link the AEDC data from 2009 and 2012 to birth data for over 150,000 children.

Nearly 10% of all the children were considered to be developmental high-risk, DHR, and the more immature the child was at birth the higher the relative risk of being DHR, which was true up to, and including, 38 weeks. At 38 weeks there was a 6% increase in the risk of a child being DHR compared to being delivered at 40 weeks.

In other studies of late preterm births, or early term births, the reason a child was delivered early were usually unknown, which has always complicated the interpretation of the results, it was never clear if the reason which led to the early delivery was the problem, or just being born early.

This study partially addresses this, but it still remains a little uncertain why labour was induced at 38 weeks rather than later. Some of the differences that they found may be due to, for example, mothers with early or established pre-eclampsia being induced at 38 weeks, or mothers with a baby showing early signs of growth restriction. the authors have tried to address this by adjusting the relative risks for maternal hypertension and for infants being small for gestational age, which is about as good as you could do with this kind of data.

f1-large2

You can see from this figure, which shows the adjusted relative risks of having DHR, that there really isn’t any difference between 39 weeks, and 40+ weeks. Once you are 38 weeks or less, there are more and more children with DHR, and at each week of gestation, spontaneous labour is associated with lower risks than induction, and the highest risk is actually having an induced labour and then ending up with a C/section.

I think it is highly unlikely that the teachers were aware of the birth history of the children, which makes this assessment practically masked, and I think a very reliable evaluation of the associations between delivery and these outcomes. Of course you can never, from observational data, ascribe causation, but it is hard to think of any other reason why you would find these associations after adjustment, other than a causative link; meaning that it seems most likely that inducing labour, or doing a caesarean delivery before 39 completed weeks, interrupts cerebral development and has long-term adverse effects.

It is also interesting that, even at 40 weeks, there seem to be some risks from having an induction or from a pre-labour caesarean. Although on an individual basis the risks are small, on a population basis this is important, and this information should certainly be included in any shared decision-making about timing of induction or elective caesarean delivery.

The lesson I think from all of this, is that you should have a really good reason for inducing labour, or performing a pre-labour caesarean. The best outcomes seem to be, even if a caesarean is planned, among babies delivered after the onset of spontaneous labour.

 

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Re-evaluating what is really friendly to babies

Posted on 9 November 2016 by Keith Barrington

Many hospitals are very proud of being “baby friendly” or are trying to achieve “baby friendly hospital” certification, under the WHO initiative.

Unfortunately many parts of that program are not evidence-based, such as (as one example) the ban on soothers (or dummies or pacifiers or whatever they are called in your part of the world). But does the baby-friendly initiative even work? Does introducing “baby-friendly” hospital initiatives (BHFI) and/or becoming certified actually improve breastfeeding initiation rates, or duration, or exclusivity?

A new systematic review, punctiliously performed as always by the USPSTF (US public service task force), actually runs to 150 pages in its original version. Fortunately a much more manageable summary of the evidence has been published in JAMA. The review was not just about the BHFI, but a review of all the interventions that have been studied to try and improve the 3 elements of breastfeeding success that I mentioned (initiation, duration, exclusivity).

Overall, the evidence shows that system-wide interventions (such as getting your hospital certified as baby-friendly) have not been proven to improve anything about breastfeeding. The evidence is rather scanty, but what exists is negative (by which I mean not that the evidence is of a negative impact, but that there is no evidence of benefit). Various individual parts of the BHFI, as system-wide approaches, have also not been shown to be  effective, either.

The system-level interventions that were evaluated within these 9 studies included receiving accreditation for the BFHI, a clinic policy to provide breastfeeding support groups for pregnant women and breastfeeding mothers, and establishing maternity care practices for maintaining mother and infant contact following delivery or restricting or delaying pacifier use. Across these 9 studies (7 RCTs and 2 before-after studies), there was no consistent evidence of an association between system-level changes and the rate of any or exclusive breastfeeding at up to 16 weeks’ postpartum.

In contrast, individual-level interventions, which include a whole host of different interventions such as individualized lactation support, educational interventions, peer counseling, and telephone support, were effective, and were maybe more effective if applied at multiple time points, antenatally and postnatally.

One of the individual level interventions which did not work in 2 RCTs was counseling to avoid pacifier use.

An editorial accompanying the USPSTF papers gives a clear interpretation of the review and the recommendations that the USPSTF makes based on them. It also includes this:

A second potentially controversial area involves use of feedings other than breast milk. Counseling mothers to avoid giving infants any food or drink other than breast milk during the newborn period is step 6 of the BFHI and one of the primary care interventions most commonly used to support breastfeeding. Three randomized trials have specifically examined the effectiveness of counseling to avoid giving newborns any food or drink other than breast milk; none showed a beneficial effect of such counseling on breastfeeding duration.

The editorial notes that these 3 studies were not included in the new SR. I checked over the inclusion criteria for the USPSTF review, and I don’t really understand why they weren’t included. It was maybe because it is an intervention that only applies to mothers who are, or were intending to, breastfeed, but that isn’t listed as an exclusion criterion in the methodology part of the 150 page document.

Avoiding any and all supplemental food or drink is potentially hazardous. A mother’s milk may take several days to “come in” and babies can get dehydrated with hyperbilirubinemia, hypernatremia (occasionally severe), and may need to be hospitalized. Those complications are strongly associated with exclusive breastfeeding. Such complications might be acceptable if there were proven adverse consequences of occasional supplementation of breastfeeding babies with formula if there is an indication to do so. But I don’t think that is proven, at all. Nor is there an evidence in this whole systematic review of impacts of the various interventions on health outcomes. Even though the individual level studies do mostly show benefits on initiation of breastfeeding, breastfeeding for at least 3 months, and exclusive breastfeeding for at least 3 months, there is no clear decrease in gastroenteritis, or respiratory infections. Which is not too surprising as few studies have actually measured those outcomes, and the observational studies showing those impacts of breastfeeding often show relatively small effect sizes in the high-resource countries where many of these trials have been done. You would really need a very large trial in a higher risk population to prove, what I think there is little doubt about, that a specific intervention which actually increases breastfeeding rates and durations will have significant health benefits.

It is because of those benefits that we need better data. Not data about the health benefits of breastfeeding, they are already overwhelming. Data about how to improve breastfeeding initiation and duration, better studies to prove what works so that we can focus our resources on effective and beneficial practices.

The avoidance of soothers/pacifiers also came up in another influential review, this time from the AAP, and about reducing sudden unexpected death in infancy, which recommends considering pacifier use at sleep times. In the text they specify that this should only be after establishment of breastfeeding, but what they mean by “well-established” is not clear, nor do they give any data that shows that early pacifier use adversely impacts on establishment of breastfeeding.

Improving breastfeeding duration requires us to be supportive of mothers who are trying their best without the extensive social supports that societies provided in the past, without a network of wet-nurses, mothers who may be surrounded by ill-informed healthcare workers, family, or friends. A mother who feels good about herself and her attempts to give breast milk to her baby, as much as she can for 3 or 4 months if she can, will be much more likely to be successful than if she is made to feel inadequate by policies or by individuals that demand perfectly exclusive breastfeeding for 6 months.

Let her give the baby a soother/pacifier/dummy if she wants, and if the feeding is not going well in the first few days, a few bottles of formula, or pumped breast milk are not only harmless, they are better than harmless, they may help the mother and her baby to get over the hump and carry on breastfeeding, rather than giving up all together. They may even get the Dad more involved, many of us like being involved in feeding babies, and feel a bit jealous when breastfeeding is going well and we are excluded!

That sounds really baby friendly to me.

Posted in Clinical Practice Guidelines, Neonatal Research | Tagged , | 4 Comments

Antenatal Steroids closer to term?

Posted on 4 November 2016 by Keith Barrington

A new systematic review in the BMJ (Saccone G, Berghella V. Antenatal corticosteroids for maturity of term or near term fetuses: systematic review and meta-analysis of randomized controlled trials. BMJ. 2016;355:i5044) includes 3 studies which examined the use of antenatal steroids in mothers at high risk of delivery between 34 and 36 weeks 6 days, and 3 studies of using antenatal steroids prior to elective section after 36 weeks.image1

The results are firstly presented with both categories combined, which I think is very questionable. I can see no clinical value in combining the 2 categories of studies, there is no overlap in the gestational ages, so the combined outcomes are meaningless. No mother could have been eligible for both of the groups of trials, which I just realized is a good criterion for deciding if you should perform meta-analysis of trials.

Barrington’s new rule for meta-analysis: If it is impossible to have been eligible for both of 2 trials, don’t combine them. Now I will have to go through my own Cochrane reviews and see if I follow my rule.

The reasoning behind the rule should be obvious, the only point of doing a Systematic Review (SR) of an intervention is to be able to answer a clinical question. Such as “if I have a baby at term with hypoxic respiratory failure should I use inhaled nitric oxide, what are the benefits, and what are the risks, compared to no nitric oxide?” So meta-analysing all the studies which randomized babies for whom that definition is accurate is appropriate.

The first 3 forest plots in the antenatal steroid SR on the other hand give an answer to a question which will be never be asked, “if I have a mother who is somewhere between 34 and 40 weeks gestation and might be high risk of delivering before 37 weeks or on the other hand might be planned for an elective caesarean delivery after 37 weeks, should I give her steroids at some point, either now or….” (I gave up trying to formulate the question).

The SR does, thankfully, go on to also provide the results of the 2 groups of trials separately, here is an edited version of table 3, which is the results of neonatal outcomes for the studies of mothers at high risk of delivery between 34 weeks and 36 6/7.

The first fractions are the results from the steroid group, the second are the controls. As you can see it really is only the multi-center MFM network trial which contributes much to the results. Don’t ask me what the column headed τ2 is, it isn’t explained in the methods.
image2

The results whose 95% CIs do not include 1.0 (no impact of antenatal steroids) are in bold. The summary measures are all relative risks, apart from the mean reduction in Apgar scores by 0.62 (I don’t recall ever seeing a baby with an Apgar score of 7.98!)

Although 40 % less severe RDS and 40% less need for surfactant sounds great, another failing of this SR is the complete lack of any calculation of absolute risk reduction or NNTs, so I have done it for you. The absolute risk reduction is from 2.4% to 1% in the Gyamfi-Bannerman trial, an ARR of .014, or a number needed to treat to prevent 1 case of severe RDS of 71 (I can’t calculate the 95% CI without putting all the numbers into another computer program), which is a lot of injections for no decrease in need for intubation, but avoiding surfactant in one baby.

The downside, as you can see from that table, is a substantial increase in the incidence of neonatal hypoglycemia, from 15% to 24%. an absolute risk increase of 0.09, with a number needed to harm of 11. Hypoglycemia is defined in the supplementary material of Gyamfi-Bannerman as a glucose at any time of less than 40 mg/dl, which is 2.2 mmol/L for those of us who use modern units. The protocol doesn’t state anything about standardized monitoring for blood sugars in the babies of the participants that I can see (the protocol is available on the NEJM website, and I read it, just to be able to write this blog post for you my gentle readers), as it was a masked study we must assume that the babies were monitored in the same way in the 2 groups, so the increase is probably a real effect of the intervention. As you can see from the first table, mothers with diabetes were excluded from this trial.

One conclusion of this analysis is therefore that there is a substantial increase in the risk of hypoglycemia, and therefore all babies born after antenatal steroids will need to be monitored for this effect, in the same way as babies with other risk factors, which is a lot of extra blood sugar monitoring and extra pain, for 100% of the babies, for a non-significant decrease in the number of babies needing mechanical ventilation of 0.6%!

I am actually quite surprised at the BMJ, who have one of the highest standards of editorial review, in my opinion, that this SR was published like this.

If we go on to the issue of steroids before elective caesarean delivery, it gets even murkier.

image3

There is no “neonatal hypoglycemia” in this table, because it wasn’t reported in any of the trials. I think we have to assume therefore that there might well be a increase in the incidence of hypoglycemia for this group of babies also, and treat antenatal steroids as a risk factor for hypoglycemia in all of the babies.

The supposed benefits of antenatal steroids are, for example a fantastic 78% reduction in severe RDS. Wow! But the reduction in severe RDS is, in absolute terms, from about 1% to about 0.25% so a number needed to treat, NNT, of over 100.

The 2% reduction in NICU admission (from 5% to 3%) gives an NNT for admission to the NICU of about 50. Some of the outcome variables are pretty dumb, 2 hours less on oxygen for example, only applies to the babies who needed oxygen to start with, and is of no real clinical importance.

As you can see from the table, in fact, the rate of admission to the NICU was not different. Which is not at all how the article by Stutchfield was actually originally reported. They claim to have a reduction of 50% of NICU admissions, but in other places in their publication they note that was a reduction in NICU admissions “for respiratory distress”, in fact the total NICU admissions were NOT different between groups, as admissions for non-respiratory disease were in the other direction, more among steroid exposed babies than controls. Maybe they were for hypoglycemia? The numbers they report for NICU admission by gestational age completed weeks, are actually just for respiratory distress, and are taken from logistic regression, not from the original data:

The predicted probability of admission at 37 weeks was 11.4% in the control group and 5.2% in the treatment group, at 38 weeks it was 6.2% and 2.8%, respectively, and at 39 weeks it was 1.5% and 0.6%.

Which means that at 39 weeks the NNT is about 111 to avoid admission to the NICU for respiratory distress, but overall admissions are not actually significantly reduced.

I do think that avoiding NICU admission is a worthwhile goal, and reducing neonatal respiratory distress is also worthwhile. But with such a small absolute reduction in these outcomes we had better be sure that the intervention is safe. Only one of these trials has tried to do long term follow up of the babies. Stutchfield sent out a questionnaire to parents of babies born in 4 of the original centers in the trial (n=about 800), only about half were returned, and about 7/8 of those also had a school questionnaire returned.

The abstract of that manuscript states:

25 (12%) children whose mothers received betamethasone had reported learning difficulties compared with 27 (14%) control children. The proportion of children who achieved standard assessment tests KS2 exams level 4 or above for mathematics, English or science was similar.

The actual data presented in the body of the article don’t report the proportion achieving those levels, which is weird, but the article does report other outcomes which are not as comforting:

image4

With the large number of comparisons made this might be a spurious finding, but it certainly should give some pause before recommending antenatal steroids for this indication, a recommendation which might apply to many thousands of mothers and babies every year.

So what are current recommendations?

In October’s Obstetrics and Gynecology the American College of Obstetrics and Gynecology have published an update to their antenatal steroid guideline.  It now states:

A single course of betamethasone is recommended for pregnant women between 34 0/7 weeks and 36 6/7 weeks of gestation at risk of preterm birth within 7 days, and who have not received a previous course of antenatal corticosteroids.

As far as I can see there is nothing about steroids for elective caesarean delivery near to term. Apart from it being in the list of things for which there are no data(!)

The Royal College of Obstetrics and Gynecology of the UK in contrast in their statement from 2010 note the following:

Antenatal corticosteroids should  be  given  to  all  women  for  whom  an  elective  caesarean  section  is planned prior to 38 +6 weeks of gestation.

I think these two guidelines are both mistaken, neither of them has bothered to look at the absolute risk reduction (or increase), the number needed to treat, or the potential harms. I think the recommendations should be much more nuanced, and note the very large number of treated women for whom there will be no benefit, that the decision should/must be discussed with the mother (who knows maybe even the father).

I think the biggest potential adverse effect of these guidelines is that the risks to the baby of a late preterm delivery will be minimized; that obstetricians, who already think that late preterm birth is unimportant in the long term, will think that they can blithely deliver babies before term as long as they give steroids.

We need to emphasize that late preterm delivery is a major risk factor, on a population basis, for adverse developmental and health issues in children.

A great review article from Betty Vohr in 2013 laid out all of the then available data showing adverse impacts of being born before 37 weeks, we now, of course, have even more data, and more reasons for concern about these infants. Another review from last year, with Elaine Boyle as first author also noted the adverse long term physical health effects of being late preterm or early term, compared to really really full term.

Including this figure for example:

image5

The impacts of late preterm, or even early term delivery should not be minimized just because we might be able to slightly reduce the risk of some short term respiratory adverse effects with antenatal steroids. Only when preterm delivery is inevitable or essential for the mother or baby should we start to weight the risk/benefit balance of antenatal steroids, which doesn’t seem to me to be a closed question: with total NICU admissions and need for mechanical ventilation unchanged, and substantially more hypoglycemia.

Posted in Neonatal Research | Tagged , , , | 7 Comments

What outcomes matter to parents? A new publication

Posted on 1 November 2016 by Keith Barrington

This new publication of ours has been an interesting process, Annie Janvier and I wrote it in collaboration with other parent representatives, Barb Farlow, who we have collaborated with previously, a mother of a little girl who had trisomy 13, and Rebecca Pearce and Jason Baardsnes, who had twins at 25 weeks, one of whom died. As many of you will know, Annie and I are also parent “representatives”, our little treasure Violette (whose hand is at the top of this blog) was born at 24 weeks gestation.

Janvier A, Farlow B, Baardsnes J, Pearce R, Barrington KJ. Measuring and communicating meaningful outcomes in neonatology: A family perspective. Semin Perinatol. 2016 In this article we discuss the outcomes that are commonly measured in neonatology, both in research, and in quality control, and for individual assessments, and ask if we are measuring the right things.

We wanted to be thoughtful and provocative (wanting to provoke change, not just strong reactions), and I think we got it right, let me know if you agree:

Dichotomous and continuous outcomes : we discuss how things which are in reality continuous outcomes, such as lung injury, or developmental delay, have been dichotomized into yes/no, good/bad outcomes, mostly for the convenience of researchers. It makes little sense to label someone who stays in oxygen until 36 weeks and 2 days as having BPD, whereas if the oxygen was weaned 3 days earlier they would not have had BPD. What is important is the impact of that lung injury on the life of the baby.

Even more problematic is combining artificially dichotomized outcomes especially combining them with death (death or BPD, for example) as if coming out of oxygen later were in some way equivalent to being dead.

Of course combining multiple artificially dichotomized outcomes is even more problematic, death or NDI being the most important example, being dead, or having a serious hearing deficit requiring hearing aids, or having a major visual problem, or being stiff on one side, or having a developmental delay which puts you below -2 SD of the population mean, are often combined, as if it was self evident that each one of those adverse outcomes were equally important. We note :

When two outcomes have potentially very different values to patients, they should be discussed separately.

So outcome data combining outcomes which are of very different individual value are of little use. Discussing the risk of death separately to the potential long-term consequences if the infant survives, may give a very different response, to the “80% risk of death or NDI”.

In the article we also discuss other important issues such as “Confusing screening tests with disabilities”, the Bayley Scales of Infant Development should be considered to be a screening test, a way of evaluating current development, screening for delays, and plugging kids into intervention programs if necessary, but NOT used as a way of defining who is OK, and who has an impairment; we know the Bayleys are very poor at prediction of longer term intellectual problems, and I know of no data that low Bayley scores are related to poor quality of life among NICU graduates.

Some outcomes which have a huge impact on families are, in contrast, minimized in neonatal outcome studies: feeding difficulties and need for home gavage feeding for example, are rarely quantified in studies but may be very disruptive for families.

We also discuss the importance of resilience, or “coping”, how many families can adapt to non-optimal outcomes, and can even benefit from them, how resilience has been undervalued in neonatal research:

… a family with a child who has severe cerebral palsy, for example, will find meaning and hope in the life of their infant, even if they wish it was otherwise. The same can be said about families of children who have home ventilation, Down syndrome trisomy 13 or 18. [for each of these examples we give references] Adaptation and coping have been measured in older patients, but neonatal research is lagging behind. Several studies have noted that the adverse impact of a child with neurological or developmental difficulties decreases markedly over the years. A recent study of families with children who have intellectual disabilities was almost universally positive about the impacts of having such a child on themselves and their family. Interventions aimed at families with poor resilience predictors could improve neonatal and parental outcomes.

We end the article with some recommendations which I reproduce below in shortened form.

Recommendations for Clinicians

1. The caregiver should themselves be informed regarding the condition, the risks, and the potential impacts of the condition for children.

2. Avoid conflating neonatal outcomes: Remember that for a parent, death is not the same as disability. Clinicians should speak about the risk of death, and then of disability in survivors.

3. Children are more than a diagnosis : Parents should not only be informed of potential adverse conditions or diagnoses. They should know what these diagnoses mean to children and families, in a practical sense.

4. Personalize the information: The information should be adapted to the needs and wishes of the family, and the precise nature of the infant’s situation. Many recommendations for antenatal counseling in extreme prematurity demand that information be standardized and that providers describe all the possible complications of prematurity.

5. Provide balanced information: Parents should be given an opportunity to ponder what a diagnosis means for them, for their family, for their future, they should be told about the positives as well as the negatives.

6. Provide information relative to follow-up programs : Parents are often not well informed of the reasons for systematic follow-up. Many parents think this is essential to identify potential problems their child may have…

7. Discuss real-life outcomes: Providers should have regular interactions with NICU parents about the life trajectory of their child: what is the next step—remove the tube, remove the CPAP, full feeds, transition to oral feeds, oximetry, etc…

8. Normality and normativity: Avoid the term “normal” when describing babies after NICU discharge. Their tests and imaging may be “normal” or “abnormal,” above or below average; but for a family—especially after the NICU experience—these babies are extraordinary.

9. Empower: Parents of all NICU children should be able to feel like good parents—doing a good job caring for their child. In the NICU, they should be congratulated when they hold their baby, visit, provide breast milk, read to their child, ask questions, etc. .

10. Inform NICU families of parental support groups or associations that can offer them experiential information about the child/family experience

11. Words are important : Know the name of the baby and avoid labels: neonates are not their condition or their outcome. The way we describe babies can have an impact on how parents see their children.

Recommendations for researchers

1. Research projects should focus on primary outcomes that are of importance to families. Families should be involved in planning research, and in determining which outcomes should be investigated…

2.Decreasing the impacts of neonatal critical illness is a vitally important task, given the improved survival of infants with so many different conditions. But unless we investigate which outcomes are truly most important to our patients and their families, we will not be able to progress further.

Posted in Neonatal Research | Tagged , | 2 Comments