Category Archives: Neonatology

VATER/VACTERL

VATER and VACTERL

Acronym for:

  • vertebral defects,
  • anal atresia,
  • tracheoesophageal fistula with
  • esophageal atresia [so should be VATOR in UK]
  • and radial dysplasia.

Nearly all cases sporadic, with no recognized teratogen or chromosomal abnormality. More common in infants of diabetic mothers.

VACTERL is the expanded syndrome, acronym for

  • vertebral anomalies, anal atresia,
  • cardiac malformations (Ventricular septal defects, Patent ductus arteriosus, Tetralogy of Fallot, Transposition of the great arteries),
  • tracheoesophageal fistula, esophageal atresia
  • renal anomalies (urethral atresia with hydronephrosis), and
  • limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb).

Diagnosis made if 3 or more defects are present.

CHARGE sequence

Stands for:

  • coloboma of the eye;
  • heart anomaly (Tetralogy of Fallot, ASD, DORV);
  • atresia choanae (failure of nasal passages to form – causes feeding difficulties);
  • retardation of mental and somatic development;
  • genital abnormalities eg microphallus (also hypogonadism, so delayed pubertal development in both sexes);
  • ear abnormalities and/or deafness.

Note that none of the letters used in the acronym are the same as used in VACTERL.

Facial palsy, cleft palate, and dysphagia are commonly associated.

The term CHARGE should be restricted to infants with multiple malformations and choanal atresia and/or coloboma, combined with other cardinal malformations (heart, ear, and genital), for a total of at least 3 cardinal malformations. Growth retardation is not one of the cardinal features.

Mostly isolated, mutation in CHD7 gene (associated with increasing paternal age).

Congenital diarrhoea

Usually severe and life threatening. May have been polyhydramnios prior to birth. Abdominal distension, even ileus at presentation, weight loss, nappy rash (if acidic stool).

In some of these conditions, symptoms improve through childhood, but may be susceptible to severe gastroenteritis.

Causes –

  • Congenital sodium diarrhoea – metabolic acidosis, low sodium. Can be associated with atresia choanae. Associated with later IBD.
  • Congenital chloride diarrhoea – metabolic alkalosis, low chloride. Treat with salt supplementation.
  • Congenital sucrase-maltase deficiency – no problem with breast milk, may not present until food aversion/intolerance emerges. Higher rates in Eskimo, where diet traditionally low in carbohydrate!
  • Congenital lactase deficiency esp Finland!
  • Congenital fructose (cf fructose malabsorption, IBS like) – hypoglycaemia, jaundice. Sucrose also triggers.
  • Glucose-Galactose intolerance – high sodium.
  • Lysinuric protein intolerance
  • Tufting enteropathy
  • Microvillous inclusion disease

Some lists include pancreatic disorders eg CF, Schwachmann-Diamond, other causes are abetalipoproteinaemia (so check lipids) and IPEX.

If diarrhoea stops with feed withholding, then osmotic rather than secretory. Anion gap (Na+K-Cl-Bic) in the stool greater than 50 (normal 10-20) indicates unidentified acidic substances.

Reducing substances in stool suggest carbohydrate malabsorption but not reliable (and test no longer made) – bacteria break down complex carbohydrates so false pos, molecular methods better.

Low albumin suggests protein losing enteropathy eg IPEX.

[ Int J Mol Sci. 2012; 13(4): 4168–4185. doi: 10.3390/ijms13044168]

CMV (Cytomegalovirus)

Congenital – Neonates

Commonest congenital infection in developed world – 0.3% of births. Assoc with STIs, breast feeding and childcare. About 40% of pregnant women seronegative. Primary maternal CMV transmits in 40%, of which 10% symptomatic. Symptomatic babies have 30% mortality, and 90% morbidity. Even asymptomatic babies have 5-15% long term sequlae esp deafness. Virus is found in all body fluids so spread by close contact. Survives in fomites for several hours, but no apparent increase in risk in health care environments cf nurseries. Transmission usually occurs during primary infection, but possible in maternal reactivation (but disease is less aggressive) – an important issue if a vaccine is ever considered. Gestation at time of infection not very important (cf toxo, rubella, etc!).

CMV positive mothers nearly all secrete CMV DNA in breast milk, even if other body fluids are negative! Main cause of postnatally acquired CMV – usually asymptomatic in term babies but can be severe in preterms. See Prevention, below.

Causes anaemia, thrombocytopaenia, petechiae, hepatosplenomegaly, pneumonitis. Can cause a sepsis-like syndrome. Also chorioretinitis, enteritis (even NEC type picture), conjugated jaundice, and/or aseptic meningitis. Later, abnormal teeth, deafness (about 12% of all cases, can be progressive but sometimes improves, major economic impact), cerebral palsy. CNS involvement can lead to abnormal tone and (rarely) seizures. Whether postnatal infection can also cause late effects is uncertain.(Pediatr 2003;143:16-25, PMID 12915819 )

Investigations

CT to look for intracranial calcifications (more sensitive than USS), opthalmology. Urine/blood PCR, culture of urine and surface swabs. IgG will usually be maternal, as usual; IgM is only 70% sensitive and sometimes gives false positives (in adults, can persist or reappear during reactivation). The presence of low/moderate avidity anti-CMV antibody indicates primary infection, and persists for about 20 weeks.

USS is vaguely prognostic: (n=57) at least 1 sequela developed in all neonates with symptoms who had abnormal US results, whereas none of the neonates with symptoms who had normal US results had long-term sequelae. Unusual to get asymptomatic babies with abnormal scans. In the population without symptoms, sensorineural hearing loss developed in 3 of 37 (8.1%) neonates with normal US results, so NPV isn’t great. (J Pediatrics Volume 150, Issue 2 , February 2007, Pages 157-161)

Guthrie PCR testing has been looked at, but sensitivity only about 70% cf urine.

Treatment

Ganciclovir gives mixed results, many studies have been uncontrolled and small. Not curative: appears that viruria always returns. Drug is carcinogenic, mutagenic, causes infertility, needs central line, 6/52 course, causes neutropenia in 63% so line infection is a big problem. For sepsis-like syndrome, treatment with Ganciclovir is worthwhile until oral valganciclovir can be tolerated. For less severe infections, the risk:benefit balance of treatment is less clear. Kimberlin RCT (n=100) chose patients with:

  • microcephaly
  • deafness
  • intracranial calcification
  • chorioretinitis
  • or abnormal CSF

Patients received 12mg/kg/d of Ganciclovir for 6 weeks. At 1 year, just 26% of untreated controls had normal hearing in their best ear. 50% of the ganciclovir group had improved hearing or maintained normal hearing cf 26% of controls (not significant). 21% of the ganciclovir group had deterioration cf 68% of controls (p=0.002). Interim results at 6 months were similar. These figures are for hearing in the best ear.

In conclusion, in a fairly small study, ganciclovir appears to help prevent hearing deterioration for at least a year, and may also help recovery of hearing impairment. The number needed to treat (NNT) is 1.91 to prevent 1 case of hearing deterioration at 6/12, and 3.66 at 1 year. There are, however, some problems with Kimberlin’s trial.

  • The intervention requires a central line, and ganciclovir causes neutropenia. Grade 3 or 4 neutropenia was seen in 64% of treated patients, although this led to discontinuation of treatment in only 4 out of the 29 patients on ganciclovir.
  • 3 patients had catheter infections.
  • There were 3 deaths in the ganciclovir group and 6 in the control group. None of the deaths was considered to be related to therapy.
  • It should also be noted that there was an extremely high drop out rate (58%) due to a combination of factors including difficulties with transport, and access to BSER testing. This drop out rate could potentially lead to confounding.
  • There was little evidence of other benefit to treatment. There was no difference in resolution of hepatosplenomegaly or retinitis. There was better weight gain and head growth at 6 weeks but this was not sustained at 1 year. A subsequent conference abstract looked at developmental delay using the Denver developmental evaluation and found significantly less delay at 12 months but neither this study nor any other longer term neurological outcome data appear to have been published, perhaps surprisingly.(Oliver et al, Pediatric Academic Societies 2006)

Valganciclovir

Valganciclovir is a prodrug of ganciclovir. It is an oral preparation. Pharmacokinetic studies have found that a dose of 16mg/kg produces a similar AUC12 (area under the concentration-time curve over a 12 hour period) to that obtained with ganciclovir. Neutropenia was still seen but was less common, perhaps because of the dosing strategy and drug level monitoring.

It is an attractive alternative to ganciclovir but there is currently no evidence to show any long term benefit. A current UK placebo controlled study aims to compare 6 weeks and 6 months of valganciclovir (16mg/kg). A randomized comparison with ganciclovir has not been attempted, perhaps due to fears of a high drop out rate.

How to counsel parents

Given the limited evidence and the complex nature of the interventions, a full discussion should be had with the parents and a treatment plan drawn up with their explicit consent.

Issues to consider are:

  • How severe is the infection? Microcephaly, petechiae, IUGR, cranial USS abnormalities are all indicators of a poor outcome. Viral load predicts asymptomatic babies at high risk of deafness.(Arch Dis Child 2008 PMID 18039747) This may increase the perceived need for intervention, or alternatively make intervention seem more hopeless.
  • How do the parents feel about the potential for deafness or other disability? Deafness is not inevitable, and may not be the most significant issue for that child. Different individuals have differing attitudes about the seriousness of potential disabilities.
  • Can parents accept an experimental treatment? Neither ganciclovir or valganciclovir are used routinely, and the evidence in their favour is limited. At the same time there is no long term safety data.
  • If treatment is considered, does the lack of evidence for valganciclovir compensate for its ease of use and better side effect profile? An initial course of ganciclovir followed by valganciclovir is another option, particularly if access or side effects are problematic.

Prevention

Postnatal infection is known to occur, ie initial screening of the baby is negative, but blood PCR turns positive after 10 days, or urine after 3 weeks of age. Breast feeding is the most likely mechanism, given that blood products for transfusions are generally CMV negative or leucodepleted. CMV can be found in the breast milk of most seropositive mothers, even though it does not appear in maternal urine/blood, so it appears to be local reactivation in the breast! There also appear to be factors in the milk that inhibit CMV (hence virolactia is not the same as DNAlactia!).

The rate of postnatal infection varies widely between studies (6-55%), as does the rate of symptomatic infection (0-75%). (Hamprecht K, J Clin Virol 2008;41:198�205.) The mean age at seroconversion is 77 days; appears to be related to maternal IgG level, and whether virus can actually be cultured from milk or not.(PIDJ 2004 PMID 15361725) In term babies postnatal infection is rarely symptomatic, but in preterm babies a spectrum of disease is seen, with some developing a sepsis syndrome, others just transient neutropenia, thrombocytopenia, and cholestasis. The severity appears to relate to gestation and birth weight (inversely related, with the highest risk in birthweights below 1000g and gestation below 30 weeks).(Maschmann J, Clin Infect Dis 2001;33:1998�2003). Evidence to date does not support any long term sequelae of postnatal infection, in term or preterm babies. Luck S, Arch Dis Child 2009;94:F58-F64 PMID 18838466 Freeze-thawing and pasteurization are quite effective at eliminating CMV from breast milk (Holder pasteurization, ie for 30 min at 62.5�C, is probably more effective) and the UK association for milk banking (UKAMB) recommends a sequence of alternate freezing and pasteurization – but immunological qualities of breast milk are affected, and cases of severe infection have still been described.(Hamprecht K, J Clin Virol 2008;41:198�205.)

Whether the breastmilk of all seropositive mothers should be treated before being given to preterm babies is unclear. Austria and France currently support pasteurization. If risk factors for symptomatic infection could be identified, then a selective policy might be the best way forward.

Prevention in utero has been tried. IVIG should theoretically work if sufficient seropositives in donating population but a RCT of its use preventively did not show significant benefit. CMV hyperimmune globulin has been given to Italian women with CMV in amnio, only 1 of 31 had an infant with symptomatic CMV at birth, as compared with 7 of 14 women who did not receive hyperimmune globulin (50 percent). Appears to be safe, and also to prevent disease in women with primary infection. Not strictly an RCT, and surprisingly high rate of CMV disease in primary infection. N Engl J Med. 2005 Sep 29;353(13):1350-62

See Euro Cong CMV initiative, who have a register of cases and are looking at whether viral load will help predict which babies do badly.

Toxoplasmosis

Caught by ingesting oocysts from cat faeces (in soil or water) or infected meat (but cats are vector). Mother to child transmission occurs only in primary infection, which is usually asymptomatic. About a third of newly infected mothers will transmit infection, but very dependent on gestational age at time of seroconversion; risk rises by 12% per week of gestational age.

Only 4% of those congenitally infected will be symptomatic.

Introduction in the UK of prenatal or neonatal screening for congenital toxoplasmosis would not be justified by the currently available evidence. 1 in 10 000 children is congenitally infected but only five in a million have severe neurological disease in infancy and some 20 or 30 per million develop brain or eye lesions by the age of 3 years… Acquired toxoplasmosis is a bigger problem than congenital (meat and meat products, in some countries water supply). (Journal of Medical Screening 2002;9:135)

Untreated congenital toxoplasmosis with generalized or neurologic abnormalities at presentation almost always develop mental retardation, seizures, and spasticity. For untreated, initially asymptomatic infants studies have found that although the mean IQ was in the average range it was significantly lower (93 versus 110); furthermore, sequelae were common – at a mean age of 8.5 years, uni/bilateral blindness (65%), sensorineural hearing loss (26%), seizures (17%), severe mental retardation (13%), and hydrocephalus or microcephaly (13%).

Early treatment is very effective. A prospective study (n=36) using pyrimethamine and sulfadiazine for 1 year beginning in the first months of life in symptomatic patients had excellent outcomes with nearly 80% having a normal IQ. Seizures, deafness and motor problems resolved in most cases. Poor prognostic factors were hydrocephalus at birth, or high CSF protein (>1g/dl), or hydrocephalus unresponsive to shunting. Other risk factors for poor outcome include diabetes insipidus, apnoea and bradycardia. Microcephaly does not always mean a poor outcome, esp if hydrocephalus does not complicate it.

In pregnancy, IgM is not necessarily diagnostic of recent infection (can persist in adults). If IgG only, probably old infection unless third trimester, so use reference lab if in doubt – do battery of tests incl dye test, IgA, agglutination. Serology not reliable if HIV co-infection. Amnio PCR only 80% sensitive and varies with gestation. Monthly antenatal USS can assess ventricular dilatation, calcification, hepatosplenomegaly. Chorioretinitis in pregnancy thought to be reactivation so not a risk to fetus.

In newborn, IgM, IgA or Sabin Feldman Dye test > 300 IU suggests infection. Avoid using cord blood in case of contamination from maternal blood. If unsure, do PCR and culture from blood, urine, CSF. Characteristic findings (in symptomatic?) are:

Chorioretinitis usually present if clinical disease, seen in 40% if subclinical. Rare in acquired disease (ie lymphadenopathy), only 1.5%.

  • chorioretinitis (always),
  • cerebral calcifications (72%),
  • hydrocephalus (44%),
  • persistent IgG antibodies beyond first year,
  • and Toxoplasma antibodies in Western blot but not present in the mother.

Other initial manifestations include jaundice (64%); hepatomegaly (50%); splenomegaly (56%); abnormal tone (58%); microphthalmia (22%); CSF pleiocytosis (56%); and abnormal CSF protein (59%).

Trial ongoing in Chicago. Regimen (Feigin & Cherry) – First 6 months: pyrimethamine – 15mg/m2 or 1 mg/kg daily else alternate days if difficult to divide tablet). Sulfadiazine – 85mg/kg in 2 divided doses, with folinic acid 5mg every 3 days, IM in young infants, 10mg if bone marrow toxicity, more frequent in young infants. Next 6 months alternate pyri/sulfa with spiramycin 100mg/kg in 2 divided doses monthly. If active chorioretinitis, high CSF protein, jaundice add steroids (pred 1.5mg/kg in 2 divided doses!) until inflammation subsiding, then taper. FBC 2x/week.

Remington + Klein regimen – pyri 2mg/ml, 2mg/kg for 2 days loading then 1mg/kg/d, 3x/wk in second 6/12, sulfa 100mg/ml, 100mg/kg in 2 divided doses, crush 10mg folinic, add to formula M/W/F, pred 1mg/kg in 2 divided doses. Fansidar 1.25mg/kg used in Europe – prob less effective levels, risk of serious adverse reactions, but convenient 2wkly dosing…

Spiramycin is good for infected mums as long as baby is not thought to be infected, where pyrimethamine/sulphadiazine are required. Prenatal treatment using spiramycin or pyrimethamine with sulfadoxine or sulfadiazine from time of diagnosis until 1 year of age has been tried. No RCTs. Metanalysis (n-1745 mothers) showed that early (within 3 weeks of seroconversion) was slightly more effective than later treatment, but that the risk was very dependent on gestation at time of seroconversion. Clinical manifestations in infected children were just as frequent whether prenatally treated or not. But difficult data and very dependent on gestational age at seroconversion. [Lancet Volume 369, Issue 9556 , 13 January 2007-19 January 2007, Pages 115-122]

Differential diagnosis: CMV, Human LCMV (lymphocytic choriomeningitis virus, found in rodents esp hamsters).

[Clin Perinatol 2005;32:705-26. Pediatrics, January 1, 1995, 95:11-20]

Galactosaemia

Actually 3 different gene defects possible, most commonly Galactose-1-Phosphate uridyl transferase deficiency (GALT, or Gal-1-PUT). The others have different phenotypes.

Presents in the newborn period after initiation of milk feeding, most commonly with jaundice, which can be unconjugated in first week but becomes conjugated thereafter. The other features listed below are seen in only a minority:

  • Vomiting,
  • poor feeding
  • Hypotonia
  • Hepatomegaly
  • Encephalopathy
  • Cataract – can be present at birth, but more usually after a week or two.
  • Sepsis – esp E coli septicaemia

Lab findings include hypoglycaemia, deranged LFTs, coagulopathy, metabolic acidosis, abnormal urine aminoacid excretion. Urine for reducing substances is not sensitive or specific. The definitive test is RBC Gal-1-PUT activity, but if a transfusion has been given alternatives are genotyping or testing the parents for carrier status.

Management is by diet. Nonetheless, neuropsych problems usually develop in adolescence and ovarian failure often occurs. Some debate about whether galactose can be tolerated from age 2-3yr.

Prolonged Jaundice

Physiological is because Long chain FAs in breast milk compete with Glucuronyl transferase! Dehydration and poor feeding contribute (jaundice FOLLOWS, does not cause). But can also be seen in bottle fed babies.

Prolonged jaundice defined as 21/7 if well, term according to American Academy of Pediatrics. After that, investigation probably appropriate.

Unconjugated vs Conjugated bilirubin is important – do direct bilirubin. Conj bili >20 may indicate significant disease, esp if unconj not high. Low albumin suggests prenatal onset.

Unconjugated

  • Haemolysis (so liver function tests normal): eg rhesus disease (diagnosis: Direct Coombs Test Positive), ABO, irregular antibodies (Kell, Duffy; varying significance), hereditary sphero/elliptocytosis, G6PD deficiency, DIC. G6PD in baby can be precipitated by maternal drugs/infection. Enzyme assay false negative because of high retic count, so test mother for carrier status.
  • Crigler Najjar is unconjugated. Uridine Di Phos Glucuronyl transferase deficiency (Dubin Johson/Rotor only present >2 yr). Recessive form is severe, assoc with kernicterus; dominant can be treated with phenobarb.
  • Hypothyroidism
  • Galactosaemia – in the first week of life can be unconjugated but always features liver dysfunction cf Crigler Najjar so unlikely to be any confusion.

Conjugated

Suggests hepatitis. Note that Alk phos in normal neonates is often high in isolation. See BSPGHAN protocol.

  • Congenital Biliary Atresia
  • Choledochal cyst: assoc with East Asians, PKD (Caroli’s disease). Cystic mass below liver. Can rupture and cause ascites, cause obstruction +/or cholangitis. Late carcinoma risk.
  • Spont CBD perforation – discoloured umbilicus, paracentesis diagnostic. Rx Surg
  • Gallstones – possible!
  • Congenital viral infection (TORCH), enteroviruses (esp ECHO, assoc with fulminant hepatitis), sepsis (eg UTI, listeria assoc with hepatic abscesses).
  • Cystic fibrosis and bile plug syndrome
  • Inherited Metabolic Disorders: galactosaemia, Zellweger’s, haemochromatosis, etc.
  • Alpha -1 antitrypsin deficiency
  • Alagille’s syndrome
  • Endocrine disorders: congenital hypothyroidism (1 in 60 000), pituitary/adrenal underactivity.

Biliary atresia

Wasting of biliary tree +/- gall bladder in early months of life (LANDING’s theory). Premature babies get it less (as wasting hasn’t progressed as much) but can still get it!

Stool colour chart

Presents with prolonged jaundice. Dark urine, pale (white!) stools distinguish it from common, benign breast feeding jaundice, but often missed. Parental reporting of stool/urine colour is unreliable! Stool colour chart available from Children’s Liver Disease Foundation.

Normally distal but 20% proximal.

Associated with SPLENIC MALFORMATION syndrome (poly or asplenia, situs inversus, malrotation, absent IVC).

Lanarkshire incidence 1.26 per 10 000, significantly higher than rest of Scotland!  NO evidence of genetic factors.  Pigweed in pregnant ewes in Australia – “biliatresone” toxin. Industrial waste…?

Investigations

Colour of stool!

Fasting (4hrs) USS essential, but sensitivity is operator dependent

Treat by Kasai Porto-enterostomy before 6 weeks ideally (16% normal LFTs, 18% portal hypertension, 94% survival @5yr +/- transplant), else liver transplant.

1yr phenobarb, urso, Vit K.  Long term Dalivit.

Consider varicella vaccination if likely for transplant!

Prognosis

Prognosis related to clearing of jaundice, established cirrhosis/fibrosis, cholangitis, biliary stricture, portal hypertension (degree of – most have).

60% clear jaundice, up to 60% require transplant in first 2yrs.  Of the rest, half need transplant in childhood, leaving just 20% getting to transition with native liver.Most mortality due to transplant complications.

New Japanese data suggests length of jaundice more important than age (traditionally 45-60 days low risk for liver failure)

Outcomes from Kasai operation are better in centres doing more than 5/yr, so only 3 supra-regional centres in England.  But outcomes in Scotland seem to have got worse, even though overall better!  Up to surgeon whether feasible or not for an individual patient.

Increased sepsis due to gut organisms from Roux-en-Y loop.

Cholangitis – features can be seen on USS.  Characteristically unwell, febrile with rise in bilirubin and LFTs (but not always).  Rx Tazocin.  Some require antibiotic prophylaxis.

Portal hypertension can develop early or late.  May present with variceal bleeding, low platelets, splenomegaly. Managed by banding of varices, TIPS shunt, transplant.

Strictures present with biliary stasis, itch, pain, coagulopathy. 

[Rachel Tayler]

Alagille Syndrome

Autosomal dominant condition (70% sporadic) with characteristic facies, biliary hypoplasia, vertebral and cardiac abnormalities. JAG1 gene.

Paucity of intrahepatic bile ducts so typically prolonged jaundice, but depending on how many ducts, may not be obvious in first few months. Jaundice gradually improves, but only minority clear completely. 30% progress to cirrhosis.

Posterior embryotoxon (white ring at periphery of cornea) is a clue, but seen in 10% of normal population so not specific.

Cardiac includes pulmonary stenosis, Tetralogy of Fallot.

Facies: broad forehead, triangular face, deepset eyes, long nose with bulbous tip.

Butterfly vertebrae characteristic (asymptomatic – see on chest x-ray).

Other:

  • Renal Tubular Acidosis, renal cysts
  • Growth failure
  • Pancreatic insufficiency