Predicting Survival Without Disability Among Preterm Infants

A recent article (J Bourke et al. .J Pediatr 2019; 215: 90-7) made me wonder if my outlook on disability-free survival of preterm infants has been skewed by the population that I encounter.  That is, the outcomes from this large Australia study were better than I would have guessed.

This retrospective cohort study identified 720.091 live births from 1983-2010; in this group, 12,083 were diagnosed with a disability and 5,662 died. The authors sought to determine rates of intellectual disability or autism as identified by the IDEA (Intellectual Disability Exploring Answers) database.  Because this is a retrospective study, it did not capture milder and more common neurodevelopmental disorders like attention deficit hyperactivity disorder.

Key findings:

The probability of disability-free survival to 25 years was the following:

  • 4.1% for those born at 22 weeks gestation
  • 19.7% for those born at 23 weeks gestation
  • 42.4% for those born at 24 weeks gestation
  • 53.0% for those born at 25 weeks gestation
  • 78.3% for those born at 28 weeks gestation
  • 97.2% for those born full term (39-41 weeks)

Risk factors for lower rates of disability-free survival:

  • Aboriginal population (instead of Caucasian), low Apgar score, male sex, low socioeconomic status, and remote region of residence

My take: This data shows the marked improvement in outcomes with longer gestation age.

Georgia AAP Nutrition Symposium 2019: Care of the NICU (Premature Infant) Graduate

This year’s Georgia AAP Nutrition Symposium featured lectures targeting the NICU graduates and children with allergies (tomorrow). My notes from these lectures could contain errors of omission or transcription.

Greg Sysyn

Link to slides: The Care and Feeding of the Tertiary NICU October 10 2019

Key points:

When can NICU graduates take a standard formula?  ‘When at normal weight at term or beyond for 2-3 months (tracking along a good percentile)’ –but keep in context (how big are parents); otherwise use preterm formula up to 52 weeks post-conceptional age. Studies have shown that formula-fed VLBW infants use of a transitional formula should continue until 3-6 months of age, possibly as long as 12 months of age.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and changes in diet should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Selective Data Mining: Reflux and Bronchopulmonary Dysplasia

With some studies, the abstract may suggest a more compelling result than is truly evident.  That’s how I feel about a recent report (Nobile S, et al. J Pediatr 2015; 167: 279-85).

Here’s the conclusion (verbatim) from the abstract: “The increased number of (and sensitivity for) pH-only events among infants with BPD may be explained by several factors, including lower milk intake, impaired esophageal motility, and a peculiar autonomic nervous system response pattern.”

To me, it sounds like this prospective study of pH-multichannel intraluminal impedance (pH-MII) of 46 infants born ≤32 weeks gestation (12 with bronchopulmonary dysplasia (BPD) and 34 without BPD) must have identified something important linking gastroesophageal reflux disease (GERD) and BPD.  But, the real findings, in my view, are that this is a negative study. Period.

Here are the results reported in the abstract:

  • “Infants with BPD…had increased numbers of pH-only events (median number 21 v 9) and a higher symptom symptom sensitivity index for pH-only events (9% vs. 4.9%)”
  • They also state: “the number and characteristics of acid, weakly acid, nonacid and gas gastroesophageal reflux events, acid exposure, esophageal clearance, and recorded symptoms did not significantly differ between the 2 groups.”

Here’s a little more data –not in the abstract:

  • The P value for the difference in pH-only events was .360
  • The authors could just have easily pointed out (in the abstract) that infants without BPD had increased acid exposure: 40.5 min compared with 27.0 min (P = .599)

What should have been in the abstract conclusion? Perhaps, the first line of their discussion: “Infants with BPD did not have significantly higher GER features compared with infants without BPD as measured by esophageal pH-MII monitoring, except for higher occurrence of pH-only events and higher SSI for pH-only events.”

The authors try to explain the differences in the BPD patients by highlighting some of the potential mechanisms of reflux and/or autonomic dysfunction.  I think the limitations of this study deserve careful scrutiny.  This was a small study with only 12 BPD infants.  There was a significant selection bias -only ‘symptomatic’ infants were included.  Some of the factors affecting BPD directly could have an indirect effect on reflux (eg. caffeine).

The authors make one other point: “we believe pharmacologic treatment for GER should be initiated only after the demonstration of pathologic pH-MII monitoring to avoid unnecessary drug therapy, adverse events, and costs.”

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Grand Prismatic Spring, Yellowstone

Grand Prismatic Spring, Yellowstone

Current Mortality from Being Born Premature

A recent study (Patel RM et al. NEJM 2015; 372: 331-40) provides prospectively collected data on 6075 deaths among 22,248 live births with gestational ages 22-29 weeks from the U.S NICHD Neonatal Research Network. between 2000 thru 2011:

Key findings:

  • Improved death rate in most recent period of study:  number of deaths per 1000 live births was 275  (2000-2003), 285 (2004-2007), 258 (2008-2011)
  • While there were fewer pulmonary deaths with time, the deaths attributed to necrotizing enterocolitis increased: number of deaths per 1000 live births was 23 (2000-2003), 29 (2004-2007), 30 (2008-2011).  Necrotizing enterocolitis was the leading cause of death between 15-60 days of life (Figure 1).
  • Overall, 40.4% of deaths occurred within 12 hours after birth.  Only 17.3% occurred after 28 days of life.
  • For the entire study period, the rate of death (per thousand) was associated with gestational age: 949 (22 weeks), 730 (23 weeks), 427 (24 weeks), 258 (25 weeks), 157 (26 weeks), 115 (27 weeks), 78 (28 weeks)
  • The authors speculate that the overall reduction in death rate is likely related to more aggressive respiratory care (for bronchopulmonary dysplasia); one marker of this was increased usage of high-frequency ventilation.

Bottomline: While there has been improvement, being born premature is associated with high mortality.

Which is Safer –Drip Feeds or Bolus Feeds in Healthy Preterm Infants?

A recent provocative study (J Pediatr 2014; 165: 1255-7) takes a look at the frequency of cardiorespiratory events in healthy neonates <33 weeks gestation who needed supplemental enteral tube feeds.

It is generally accepted that continuous or “drip” feedings are less likely to provoke reflux events (and reflux-induced cardiorespiratory events) by limiting the amount of formula in the stomach at any time point.  If there is less formula, presumably there would be less stomach distention and a lower likelihood of reflux.  In addition, a continuous amount of formula would serve to buffer stomach acid.

Despite the sound theoretical underpinnings, is this really true?  In this study, the authors detected fewer cardiorespiratory events with polysomnographic monitoring in healthy premature neonates who were fed with bolus feedings rather than with drip feedings.

Study design: Each of 33 infants served as its own control.  During a 6-hour monitoring period, noninvasive polysomnographic recordings were performed.  Each infant was fed twice via an orogastric tube.  The first meal was given as a 10-minute bolus (by gravity) and the second was delivered over 3 hours. It is noted that the tube was removed after the bolus feeding (this is not routinely done in clinical practice).

Demographics: Median gestational age was 31 weeks and median postnatal age was 16 days.  Fortified human milk was given in 12, premature formula in 7, and 14 had mixed feeding.

Results (Table 2): “continuous feeding was associated with a greater number of prolonged apneas and apnea-related hypoxic episodes.”

  • Median Apnea Frequency: 4 in continuous versus 2 in bolus group (no obstructive apneas were noted)
  • Median hypoxic episodes: 3 in continuous versus 2 in bolus group.

The authors speculate that leaving the tube in place for continuous feeds could increase GER-related apnea or trigger ‘protective upper airway reflexes in response to the irritating stimulus.’

Bottomline: The assumption that continuous feedings will reduce cardiorespiratory events is not supported by this study.  The findings warrant cautious interpretation; the small sample size and specific ages of the premature infants are significant limitations.   In addition, leaving an enteral tube in place after a bolus feeding would be a better design as this is a routine practice.

Related blog post:

Biliary Atresia More Common in Preterm Infants

During my fellowship, one of the faculty presented an abstract indicating that 4 out of 40 preterm infants with cholestasis had significant underlying liver disease in addition to parenteral nutrition associated cholestasis (PNAC).  One of these patients had biliary atresia.  The obvious point was not to assume that the cholestasis was due to the usual suspects found with premature infants.

A recent study indicates that biliary atresia (BA) in Taiwan is more common in preterm infants than in term infants (J Pediatr 2013; 163: 100-3).  The authors identified 197 cases (166 term infants) of BA between 2004-2010. This retrospective study used a nationwide screening for BA (the national stool card registry center database) along with reports from surgeons of the Taiwan Biliary Atresia Study Group.


  • Annual incidence of BA per 10,000 live births was 1.43 and 2.37 for term and preterm infants respectively.
  • Kasai operation before 60 days occurred in 68.7% of term and 44.4% of preterm infants.  Mean age of Kasai was 52.9 days for term infants and 71.8 for preterm infants.
  • Major congenital anomalies along with BA were more common among preterm (18.5%) than term (4.1%).
  • Mean onset of clay-colored stools among preterm infants was 33.6 days compared with 29.6 for term infants.
  • Stool cards had good sensitivity in detecting BA in both preterm and term infants: 96.3% and 92.8% respectively.
  • Jaundice-free at 3 months following Kasai was 62% of term infants and 37% of preterm infants.
  • 18-month survival with native liver was 72.7% in term infants and 50% in preterm infants.

While the authors point out several studies that have shown prematurity is an independent risk factor associated with BA, nevertheless this idea is counter to conventional wisdom that BA patients are typically well-appearing term infants at the time of diagnosis.  The authors also note that despite delayed diagnosis in preterm infants, this was not correlated with an impact on jaundice-free status 3 months following surgery.  This finding, in particular, should be cautiously interpreted as there were only 27 infants in the preterm group.

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