Outcomes of Liver Transplantation in Small Infants

A recent study (H Yamamoto et al. Liver Transplantation 2019; 25: 1561-70) provides data on the outcomes of infants who underwent liver transplantation (LT) in the United Kingdom (King’s College Hospital).

A total of 64 infants underwent LT (1989-2014) at a single institution. The authors compared “extra-small” (XS) infants in the first 3 months of life to “small” (S) who were 3-6 months of age.

Key findings:

  • Acute liver failure was the main indication for LT in the XS group (n=31, 84%) compared to the S group (7, 26%)
  • Hepatic artery thrombosis and portal vein thrombosis were similar in both groups: 5.4% and 10.8% in the XS and 7.4% and 11.1% in the S group
  • Bilary stricture and leakage were similar: 5.4% and 2.7% in the XS and 3.7% and 3.7% in the S group
  • 1-, 5-, and 10-year survivals were 70.3%, 70.3% and 70.3% in the XS group and 92.6%, 88.9%, and 88.9% in the S group (not statistically significant)

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Quebec City, Frontenac Hotel and Boardwalk (early in the day)

Biologic Exposure Prenatally and Perinatally

The widespread use of anti-TNF therapy for inflammatory bowel disease has improved clinical outcomes including fewer surgeries, hospitalizations, and complications.  One consequence of this usage has been the exposure of infants to biologics due to their usage by their mothers during pregnancy.  A recent study (M Julsgaard et al. Gastroenterol 2016; 151: 110-19) explores this topic further.

In this study, the authors prospectively followed 80 pregnant women: 36 received adalimumab & 44 infliximab. In addition, 39 received concomitant thiopurine therapy.

Key findings:

  • The time from last exposure to anti-TNF agent correlated inversely with the concentration of these drugs in the umbilical cord and in mothers at the time of birth.
  • Median ratio for infant: mother drug concentration at birth was 1.21 for adalimumab and 1.97 for infliximab.
  • Mean time for drug clearance: 4.0 months for adalimumab and 7.3 months for infliximab. Drugs were not detected after 9 months of life for adalimumab and after 12 months of life for infliximab.
  • No increased risk of adverse pregnancy outcomes were identified; preterm birth was low (n=3 or 3.8%). 48% of women experienced a disease relapse during pregnancy.
  • In this small study, the relative risk for infection was 2.7 in infants exposed to combination therapy.  Benign courses of viral infections were noted in 16 (20%) of the entire cohort and of bacterial infections in 4 (5%).

The authors recommend avoidance of live virus vaccines in biologically-exposed infants for up to 1 year unless drug clearance has been documented. Currently, this would affect only rotavirus vaccination.

My take (borrowed from editorial pgs 25-26): “For now, the sum of evidence seems to support continued use of anti-TNF therapy in pregnancy when clinically indicated and, despite measureable levels in offspring, there does not seem to be a significant clinical consequence.”

Related study: “Adverse Pregnancy Outcomes among women with inflammatory bowel disease: a population-basd study from England” Inflamm Bowel Dis 2016; 22: 1621-30. The authors identified 1969 pregnancies from a total of 364,363 singleton pregnancies.  Women with Crohn’s had increased preterm births with an Odd ratio of 1.42, babies with low birth weight (OR 1.39); women with ulcerative colitis had only a small increase risk in preterm birth (absolute risk <2.7%).

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Art at Big Creek Greenway, Alpharetta

Art at Big Creek Greenway, Alpharetta

Antivirals Reduce Vertical Transmission of Hepatitis B

Chelsea Market, NYC

Chelsea Market, NYC

The latest study that shows antivirals interrupt hepatitis B viral (HBV) transmission from mother-to-infant: H-L Chen et al. Hepatology 2015; 62: 375-86.

In this open-label, non-randomized controlled study from Taiwan, the researchers recruited women to receive tenofovir (TDF) at a dose of 300 mg once a day (n=62), initiated from gestational age 30-32 weeks until 1 month following delivery, and compared them to a control group (n=56).  There were high levels of viremia with HBV DNA ≥7.5 log10 IU/mL. All infants received HBV vaccination and HBIG within 24 hours of birth.

Key findings:

  • Infant transmission of HBV was reduced: at 6 months of age, infant HBsAg positivity was 1.54% versus 10.71%, P=0.0481).  At delivery, HBV DNA positivity was noted in 6.15% compared with 31.48% of the control group.
  • Maternal ALT was improved in the TDF group. ALT elevation more than two times the upper limit of normal for ≥3 months occurred in 3.23% compared with 14.29% of controls.
  • Adverse effects: only mild to moderate (self-limited) gastrointestinal and skin symptoms were noted. No fetal abnormalities were identified.

Bottomline: Antivirals, including both tenofovir and telbivudine, reduce vertical HBV transmission with a favorable safety profile.  The use of antivirals is complementary to standard prevention which consists of providing Hepatitis B immune globulin and Hepatitis B vaccine to infants of HBV-infected pregnant women within 12 hours of birth.

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GERD Treatment in Infants: “Friend or Foe”

From a recent JAMA Peds editorial: (JAMA Pediatr. Published online August 18, 2014. doi:10.1001/jamapediatrics.2014.1263)

An excerpt:

Gastroesophageal reflux disease (GERD) is common in infants and children and has been estimated to affect as much as 3.3% of the pediatric population.1 Despite this, we still struggle with the management of GERD. With a growing body of literature that illustrates a lack of efficacy and alarming adverse effects, there is increasing reason to limit the empirical use of acid suppression therapy in children.

Other points highlighted in this editorial:

  • 36% of pediatricians prescribe PPIs for infants with uncomplicated regurgitation -“despite evidence and recommendations against this approach.”
  • 39% of pediatricians prescribed proton pump inhibitors (PPIs) for infants with unexplained crying
  • Conditions predisposing a child for severe GERD include those with neurological impairment, repaired esophageal atresia, cystic fibrosis, hiatal hernia, repaired achalasia, and lung transplantation.
  • In the related article ((JAMA Pediatr. doi: 10.10001/jamapediatrics.2014.1273), the authors reviewed 8 studies of histamine-2 receptor antagonists (H2RAs) and noted no improvement in overall symptoms infants.  In older age groups, H2RAs were more effective than placebo in symptom reduction, and histological healing.

Take-home message: “It is becoming clearer that in many circumstances, prescribing acid-reducing medication to infants is doing no good and increasing the risk of harm.”

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Do medicines work for GERD infants?

“Absence of evidence is not evidence of absence.” Carl Sagan

If medicines work for infantile GERD, it is difficult to prove (Winter H, et alJPGN 2012; 55: 14-20).  The cited study is the latest having difficulty proving that proton pump inhibitors are effective in infants.  In this randomized, double-blind, placebo-controlled multinational study from 33 centers, 98 infants (1-11 months) were enrolled.  My colleague, Dr. Benjamin Gold, was one of the researchers.  Initially, a 2-week open-label treatment was given which was followed by a 4-week randomized phase.   Study participants had to have a clinical diagnosis of GERD with at least one GERD symptom  –at least twice per week in a 4-week period:

  • vomiting/regurgitation
  • irritability
  • supraesophageal manifestations (cough, wheeze, stridor)
  • respiratory symptoms triggered by feedings
  • feeding difficulties

The treatment administered was weight-based dosing of esomeprazole:

  • 3-5 kg:     2.5mg
  • 5-7.5kg    5mg
  • 7.5-12kg  10mg

Daily symptoms were captured with an interactive voice response system.  Among the initial 98 patients enrolled, 80 reached the randomization phase.  During the initial 2-week period, 81 (82.7%) had symptom improvement based on physician global assessment.  During the double-blind phase, 48.8% of placebo-treated patients and 38.5% of esomeprazole-treated patients discontinued therapy due to symptom worsening.  While the time for discontinuing esomeprazole was longer in a posthoc analysis, the primary outcome, discontinuation rate, was not significantly different.

So what is the reason that this was a negative study?  While the reasons are unclear, all of the following are possible:

  • Patient selection/lack of accurate diagnosis.  Mixed-population was recruited for the study –though this type of population is similar to clinical practice.
  • Dose of esomeprazole.
  • Inadequately powered study.  If the effectiveness of PPIs is small, a much larger population is needed.
  • Maybe these agents don’t work in infants.  Infants secrete less acid than children and adults; thus, acid blockers may not work as well. (The Medical Pendulum and Gastroesophageal Reflux)

Why not give PPIs even if they don’t work?  The previous link discusses many of the potential adverse problems that are possible with medical treatment of GERD. However, even if a medicine does not harm does not mean you should do something because it ‘might’ do some good.  An example of this is the apocryphal tale of the famous pianist who died one day in the middle of a recital. (I saw this in a journal article but cannot remember the reference.)  The manager came out to announce his death.  A man in the audience shouts, ‘Give him an enema.’ Initially, the manager tries to ignore him. After the man yells this three times, the manager responds, ‘the poor man is dead…what good will an enema do?’ The voice replies, ‘What harm will it do?

Additional references:

  • -JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placebo in withdrawal rates due to lack of efficacy. n=128.
  • -NASPGHAN 2009, Abstract#21. Meds/Rx of NICU pts did not shorten hospital stay or promote wt gain, n=1149. Abstract#26. prevacid more effective than ranitidine in infants.
  • -J Pediatr 2009; 155: 601 (letter). Should not be used to treat symptoms unless proven to be reflux.
  • -JPGN 2009; 49: 498. GERD guidelines.  “In infants and toddlers, there is no symptom or symptom complex that is diagnostic of GERD or predicts a response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatr 2009; 154: 514-20.)  Reflux is “not a common cause of unexplained crying. irritability..in otherwise healthy infants.” “There is no evidence to support the empiric use of acid suppression for the treatment of irritable infants.”