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Air pollution

General paediatrics, Respiratory

According to the 2010 Global Disease Burden Assessment, outdoor air pollution caused more than three percent of the annual disability and life lost. Rising due to urbanisation. Responsible for 50 000 deaths annually in the UK.

Air pollution associated with low birth weight, smaller heads, developmental disorders eg autism, type 2 DM, strokes, heart attacks (atherosclerosis), cognitive decline, slower development of lung function with reduced adult capacity (implication for COPD), onset of asthma, wheeze. Not just exacerbations of chronic lung disease!

Different kinds of pollution – particulates (different sizes eg PM1), nitrogen dioxide, sulphur dioxide.  Most PM10 from traffic, but natural sources too eg pollen, soil.  Wood burners! NO2 and SO2 falling as fewer power stations and less industrial output, but NO2 particular problem for urban centres where most commercial vehicles run on diesel.

Diesel engines also produce polycyclic aromatic hydrocarbons eg BaP (Benzo pyrene), maternal exposure a concern as linked to mental health and neurodevelopmental problems in children. Some also carcinogenic.

Particulates a problem for respiratory conditions. Often contain spores and pollen. Ozone associated with airway hyperresponsiveness.

Not just about degree of pollution – metereological factors (temperature, atmospheric pressure, low humidity etc) complicate. In Taiwan, pollution synergistic with dust mites for development of asthma.

Carbon deposits found in fetal side placental macrophages. 

MRSA and stenotrophomonas colonization in CF associated with maternal PM levels.

European study of 325 000 adults found mortality increased proportionally with levels of particulate matter, nitrogen dioxide and black carbon – even at levels below current EU/US/WHO standards. [BMJ 2021;374]

Southern California reduced PM levels and found less severe chronic lung problems.

1 hour commuting in Sao Paolo estimated to be equivalent to  5 cigs/d.  In London, travel to school is bulk of exposure (plus school breaks! Note locations!) esp stationary traffic.

What cars produce in lab tests is not the same as in the real world, even when manufacturers don’t cheat!

Low emission zones generally exclude cars, and may just divert traffic elsewhere, not much evidence that they help. London low emission zone has reduced NO2 slightly only.  Plan for ultra low zone. 

[Abigail Campbell, SPRING meeting 2019, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016370/ ]

Medical Error

Clinical governance, Generic

See Bawa-Garba case.

In a complex system, some errors are unavoidable. Their incidence can be reduced by better system design but they cannot be eliminated.

An error may have been the result of a decision, that could have been made differently, but when people are trying to work in an under-resourced and overstretched system, errors may be difficult to avoid.

Deterrence should therefore not involve criminalisation, but those who can influence the system eg managers and service directors.

Many errors are minor and inconsequential, but James Reason’s Swiss Cheese model highlights how a number of errors can align to enable more serious harm to occur.

In cases of “gross negligence”, the prosecution must establish beyond reasonable doubt that the failures caused the death. Unfortunately, a not guilty verdict may suggest that care was adequate. Prosecutions focus on the individual, not on the wider team or the healthcare system.

Good Practice

  • Families should receive open disclosure and an apology
  • If possible, the harm should be treated as a priority
  • When relevant, compensation should be paid
  • Appropriate mechanisms should be in place to hold to account those responsible for delivery of care
  • Punishment may be appropriate but should be proportionate to the moral culpability of the behaviour, not the outcome of complex clinical problems
  • Responses to problems should be timely – complex systems need repeated and rapid adjustment. Not served well by lengthy investigations.
  • Motivated staff should be afforded the safety of a “just culture”, rather than “no blame” or “who’s the one to blame”.
  • Culture of safety from health minister to most junior

Legal basis

According to the Bolam judgement, if a doctor has acted according to proper and accepted practice (standards of one’s peers), s/he is not guilty of medical negligence (even if some disagree with that practice); whereas the Bolitho judgement adds that practice must however be logically defensible – it’s not enough just that others do it!

Montgomery vs NHS Lanarkshire –

Bellshill shoulder dystopia and CP – Supreme Court overruled previous judgment. “Whether a risk is material should not be reduced to percentages”, nor should it be simply for the doctor to decide. “Would a reasonable person in the patient’s position be likely to attach significance to a risk?” Or does the doctor have reason to think the particular patient might feel it was significant?  That is the test of “materiality”. 

Patient does not have to ask specific question. Indeed, responsibility for concerns to be explored. 

Does not mean patients must be bombarded with information, must be comprehensible. 

Official verdict is as follows:

  • Doctor is under a duty to take reasonable care to ensure that her patient is aware of any material risks involved in any recommended treatment, and of any reasonable alternative or variant treatments.
  • The test of materiality is whether, in the circumstances of the particular case, a reasonable person in the patient’s position would be likely to attach significance to the risk, or the doctor is or should reasonably be aware that the particular patient would be likely to attach significance to it.
  • The significance of a given risk is likely to reflect a variety of factors besides its magnitude: for example, the nature of the risk, the effect which its occurrence would have upon the life of the patient, the importance to the patient of the benefits sought to be achieved by the treatment, the alternatives available, and the risks involved in those alternatives. The assessment is therefore fact sensitive, and sensitive also to the characteristics of the patient.
  • What amounts to a material risk and the skill and judgement required in explaining risks to the patient is for the Court, and not the medical profession, to judge.
  • To prove a breach of duty to advise and warn, a pursuer does not require to prove that no doctor of ordinary skill would have failed to have given her advice, if acting with ordinary care, as supported by medical opinion.
  • A patient may decide that she does not wish to know what her risks and options are.
  • The “therapeutic exception”, which allows a doctor to withhold information from a patient only applies if its disclosure would be seriously detrimental to the patient’s health, or in circumstances of necessity, such as where the patient is unconscious or unable to decide.
  • Causation continues to be based on a subjective test: what the pursuer was likely to have done, had she been warned and advised properly. To prevent hindsight bias, this will require to be tested by other evidence.

Interesting that language of consumers and choice was used in judgement, as if these decisions are simply a matter of providing information and allowing rational judgement – when lots of evidence to say that isn’t how people behave in practice!

Don’t call me brave

Communication, Generic

Often said to children when they are sad or frightened. But doesn’t help, only makes it seem wrong to have feelings.

Sometimes you need to take a break. And hovering in the doorway doesn’t count.

It can feel like there’s nowhere safe in hospital, that no one understands you. Does being brave mean keeping quiet for the happiness of others?

Instead of calling someone brave, maybe try pointing out that grown ups can feel scared too. Have you explained what the test is for, and why it is needed? Have you apologised for making them upset?

Three strike policy can help an anxious child feel respected and in control.

[Sophie Lyons, BMJ 2018;360:k1299]

Writing a statement

Clinical governance, Communication, Generic

  • Include full name, qualifications, job title and how long you have been doing it.
  • Don’t assume reader knows anything about the case
  • Use first person
  • Who did what, why, when
  • Concentrate on your observations and your understanding (no need for long quotes of what was said to you, which is what a clinical report would require)
  • Say what you found, but also what you looked for and didn’t find
  • If you’re not exactly sure what you did, and nothing documented, acceptable to say “My normal practice would be…”
  • When you have referred to or discussed with someone else, give their name and who they are, describe what they did on the basis of the notes and your understanding, but don’t comment on the adequacy or otherwise of their performance.
[https://www.themdu.com/guidance-and-advice/guides/writing-a-report-for-the-coroner]

Cardiomyopathy

Cardiology, General paediatrics

Uncommon, but often tricky to recognise, potentially lethal.

Multiple causes:

  • Viral esp enterovirus
  • Genetic
  • Metabolic
  • Autoimmune
  • Chagas, Diphtheria important in other countries

Presents with anorexia, vomiting, breathlessness. Can be abdo pain (gut ischaemia?). Chest pain unusual, young children may struggle to describe anyway. Syncope or palpitations if arrhythmia. Confusion and agitation if acidotic.

Heart will eventually enlarge but may not be apparent initially. Inappropriate tachycardia; breathlessness with clear lungs and CXR (not always acidosis), esp with exertion. Hypotension.

May be new murmur eg MR if heart enlarged.

Small complexes, ST changes, q waves on ECG. Troponins may be high, LFTs deranged, renal impairment as secondary effects.

Echo diagnostic.

Start inotropes (peripheral possible). Various mechanical aids eg Berlin Heart, ECMO.

Pyloric Stenosis

General paediatrics, Surgical

Pylorus is the name of the outflow tract of the stomach, the muscle in the wall controls how quickly the stomach empties.

For some reason, this muscle can become hypertrophied in the first month or two of life, to the point that the baby begins to vomit with feeds, become dehydrated and lose weight. Remains hungry of course, which may not be the case with some of the differentials.

The vomit is non-bilious of course, as the obstruction is above the bile duct.

4 male:1 female. Less common in black/Asian groups. Maternal history is more significant than paternal! NB Associated with TOF, other abnormalities. Associated with erythromycin use in infancy, particularly in first 14 days of life.

1st week to 5 months, but usually after 3 weeks. Only 6% present within 14 days of life – increasing proportion over time? (Even before US available) More likely to have family history?

Preterm babies make up only 3% of cases, and symptoms/signs tend to be less dramatic. Unclear whether USS criteria (below) are valid for preterms. [Arch Peds Adol Med 1996]

Diagnosis

Peristalsis may be visible through abdominal wall. Olive shaped mass (2 cm diameter) felt RUQ just lateral to midline, under liver (sit on left side), after vomit.

When well established vomiting, hypochloraemic, hypokalaemic alkalosis characteristic (but not 100% specific).

On ultrasound scan, muscle thickness more than 3mm, transverse pyloric diameter more than 14mm (length similarly) – ie 3.14 (Pi, the mathematical constant)! [radiopaedia]

Differential diagnosis = reflux, sepsis, cow’s milk intolerance, other surgical condition eg malrotation, raised intracranial pressure, Congenital Adrenal Hyperplasia, biochemical imbalance eg renal tubular acidosis, inborn error of metabolism etc.

Treatment

Surgical pyloromyotomy (Ramstedt’s)- usually laparascopic. Quite a minor procedure, since the muscle is incised and then left to heal without any need to enter bowel itself or repair anything.

Infantile spasms

General paediatrics, Neurology

Range of different shudders and twitches seen in babies and infants. Shudders and stereotypy can be dramatic, self stimulating behaviours, many kinds! Esp at 6-9/12, triggered by excitement but can also be boredom! So context important.  Can have a few together, but cluster would suggest epileptic.  Looks well. 

Differential is myoclonus, spasms (where at start may appear neurologically normal).

Infantile spasms are easy when classic, but are often atypical so can be difficult! 90% present before age 1, typically 3-7 months. Usually followed by upset so often confused with colic. Mostly when awake, arousal. Clusters of synchronous flexor spasms, usually of legs but possibly of head on torso. Definition is 0.5-2secs, so longer than jerk, some people think of an initial fast contraction followed by slower phase. Salaam attack is flexion of head and legs plus adduction of arms into midline. Rarely extensor, or mixed flexion of trunk and extension of limbs. Subtle presentations may just be chin. Can be unilateral.

Needs EEG to be sure, and even sleep EEG at that.  Low threshold since urgent treatment required.

Making diagnosis is urgent, as better initial control (in those without underlying aetiology) seem to have better developmental outcome). 

West syndrome – described by neurologist in his own son. Combination of spasms, developmental regression and hypsarrhythmia (see below). May initially be developmentally normal, become less visually attentive.  Flexion of head and trunk, arms extend/flex, abduct/adduct (can be asymmetrical if underlying hemiplegia).  Briefly upset or dazed, may be grimace.  On waking or falling asleep. Various Youtube videos available.

Rarely metabolic (consider PKU, Menkes, molybendum cofactors along with others). More often structural esp tuberosclerosis (TS – about 70% ) but also lissencephaly. Can be acquired eg post meningitis or congenital infection. Associated with Downs syndrome (actually more responsive to treatment).  Do Woods lamp and genetics. 20% cryptogenic.

Investigations

EEG by definition is abnormal, but in early phase standard awake EEG may be normal so consider sleep EEG.  Classical hypsarrhythmia in 50-70% = chaotic, high voltage.  But can be asymmetric.  If structural lesion, may be burst suppression (sudden high voltage then brief flattening) or focal features.

Treatment

ICISS (2016) showed combination of steroids and vigabatrin superior to either alone. High doses of both needed. ACTH or prednisolone at prescriber’s discretion (ACTH is alternate day injection, expensive). 

Visual field loss with vigabatrin is seen in adults on long term treatment.  Weaned as soon as possible. Side effects with both common, esp infection. 

Not yet clear if resolution of EEG findings important. Spasms settle by mid-childhood as neurodevelopmental delay evolves, most develop other epilepsy eg Lennox Gastaut. Treatment is often difficult, and most children do not have a good neurological outcome (with or without underlying brain disorder). [Cochrane Rev. PMID: 18843624]

Remember to avoid live vaccines after high dose steroids, varicella prophylaxis.

Mechanism for steroids not understood!

Hyper IgE Syndrome

General paediatrics, Immunology, Infectious disease

This is a rare, autosomal dominant (sporadic) immunodeficiency characterized by:

  • recurrent staphylococcal skin infections (cold abscesses)
  • lung infections causing pneumatocoeles, which then invite aspergillomas
  • mucocutaneous candidiasis
  • eczema, eosinophilia and high IgE

PLUS bony abnormalities:

  • osteopenia and spontaneous bone fractures
  • dysmorphism: triangular jaw, wide nose, asymmetrical face
  • dental abnormalities eg retained primary
  • hyperflexibility and scoliosis

Also called Job’s (because of the Bible story, smitten by boils etc, but could equally have been CGD!) or Buckley syndrome.

Caused by STAT3 defect, part of IL6 receptor. Not actually an immunoglobulin problem! Not to be confused with Hyper IgM syndrome. But if antibiotic prophylaxis is ineffective, IVIG is sometimes used.

An autosomal recessive form without the bone abnormalities but with vasculitis esp CNS involvement described.

Short Stature

Endocrinology, General paediatrics, OPD

Are they really? Plot height and weight, and check figures if in doubt!

Investigate if:

  • Severe short stature = height below the 0.4th centile
  • Height more than 2 centile spaces below the mid-parental height
  • Downwards crossing of more than 1 height centile in 1 year, in a child aged 2 years or over

Is there evidence of chronic disease? Needs full history and examination, including urine dip. Common things would be renal failure, coeliac disease, IBD, hypothyroidism. Endocrine causes tend to produce relatively heavy children, other chronic diseases tend to produce relatively slight children.

Brain tumour symptoms?

Are they dysmorphic? Is one parent dysmorphic? Main syndromes to look out for:

  • Turners – besides short stature, webbed neck, characteristic facies, short metacarpals, broad chest with widely spaced nipples, hyperconvex fingernails and toenails (but can be missed); decreased growth velocity and delayed puberty
  • Short limbs – SHOX mutations eg Leri-Weill dyschrondeostosis but milder variants. Classically mesomelia (short proximal bones) and Madelung deformity (wrist) but these may only become obvious in later childhood.
  • Achondroplasia or hypochondroplasia (FGFR3 (Fibroblast Growth Factor Receptor 3) mutations)

Bone age will be delayed in all except familial and idiopathic. Progressively falls behind in endocrine disorders.

Causes

Constitutional delay – good weight at birth, then “catch down” growth, dropping through centiles in infancy. Growth velocity is then normal, but with delayed bone age and delayed puberty.

Small for gestational age babies tend to catch up in first few years of life with their genetic potential, but can take up 4 years or more. 10% however remain small (more than 2 SDs below MPH) through life. Consider other causes if no catch up in first 6 months of life or still small at 2 years.

Growth hormone deficiency – can be congenital or acquired (head injury, meningitis etc). Early growth tends to be normal (growth hormone doesn’t contribute much in first few years of life). Look for hypoglycaemia in neonatal period, microphallus, midline facial abnormalities.

Investigations

  • Karyotype if dysmorphic or if girl
  • TFTs
  • IGF1 – screening test for Growth hormone problems, but may need GH stimulation testing as limited reference ranges in under 2s
  • FBC, U&Es, LFTs, Vit D, Ferritin
  • TTG antibody
  • LH/FSH, testosterone, oestradiol if pubertal signs
  • Urinalysis
  • Bone age if thinking constitutional
[SPEG Guideline]

CMV (Cytomegalovirus)

Congenital

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.