Sarah Davies. Managing Gastro-Oesophageal Reflux Disease, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.29563
Isobel is a 10 week old, exclusively breast-fed, baby girl. She is brought into the Emergency Department with a history of frequent vomiting and poor weight gain. Her examination is normal, but when you ask Isobel’s exhausted-looking mother to put her to the breast, she becomes fractious and fussy, pulling away, arching her back, and taking very little feed at all.
What are you going to do?
At face value, this familiar presentation sounds like gastro-oesophageal reflux disease (GORD), although the differential for a ten-week old with vomiting and weight loss is wide.
Gastro-oesophageal reflux (GOR) is …the effortless retrograde passage of gastric contents into the oesophagus, with or without overt regurgitation.
It is:
- Physiological, due to low tone in the immature lower oesophageal sphincter
- Common, occurring in up to 50% infants under 6m
- Frequent – can happen up to x6/day
Gastro-oesophageal reflux disease (GORD) can be diagnosed clinically when GOR is accompanied by troublesome symptoms that affect everyday functioning (eg crying, back-arching, food refusal) and may lead to complications (eg failure to thrive).
Alternative diagnoses should be considered when there are additional red flag features (see below) indicative of a different pathology and under these circumstances, investigations should be tailored to rule these in or out.
As Isobel has symptoms of GORD with faltering growth you check her head circumference (which is appropriate), dip a urine (which is negative), and send some bloods for a faltering growth screen (although you strongly suspect they will come back as normal). You explain to Isobel’s mother that there is a stepwise approach to the management of GORD starting with non-pharmacological measures.
So, in the absence of red flag symptoms, do I need to prove its GORD?
In short, no. There is no single gold standard test for the diagnosis of GORD, hence the emphasis on clinical diagnosis.
Invasive testing does have a place, though it is rarely the job of an ED clinician to be considering this.
Endoscopy is used under the guidance of a Paediatric Gastroenterologist, for infants who fail to respond to optimal medical management. This will diagnose erosions and eosinophilic oesophagitis.
pH MII (multi-channel intraluminal impedance) monitoring is used in children whose symptoms persist despite optimal medical therapy with normal endoscopy. For a great explanation of this technique this previous DFTB post on reflux from 2016.
Barium is out. Reliable biomarkers don’t yet exist. Scintigraphy, ultrasound and trial of a proton-pump inhibitor (PPI) are not useful in babies.
OK, so I only need to investigate if I think there may be another cause for the symptom. But what should be my initial approach to treatment?
- Positional management?
- Avoiding overfeeding?
- Thickening feeds?
Positional management – keeping the baby upright after feeds and elevating the head of the cot to sleep – is often advised for reflux. However, a study by Loots and colleagues in 2014 showed that regurgitation was only reduced through the use of side-lying positions which should NEVER be recommended due to the increased risk of SIDS. Head elevation made no difference at all despite some evidence that it can be beneficial in adults.
And whilst a common-sense approach would support a move to smaller more frequent feedings and keeping a baby upright for 20-30 minutes after a feed, there isn’t any good quality evidence that confirms this.
Feed thickeners have been shown repeatedly to reduce the frequency of visible regurgitation episodes in babies with reflux and in some studies to decrease cry/fuss behaviour too. They are safe and come highly recommended as a first-line intervention for babies with troublesome reflux. If you are going to advise a thickener for a breastfed infant, it’s important to suggest a carob bean-based product, such as Carobel, because the amylase in breast milk will digest the rice cereal-based thickeners such as Cerelac.
Acupuncture, probiotics, massage, hypnotherapy have not yet been adequately studied for us to say one way or another if they are of any benefit. And alginates, probably the most familiar to us being Gaviscon? We’ll cover those shortly.
The key thing to remember for any intervention, is to reserve these for your patients with GORD. Happy, thriving, refluxy babies, typically outgrow their symptoms as they transition to solid food and should be left well alone.
OK, but what if my patient has tried these already? What should I advise next?
First, check how long they have persisted with the intervention.
One of the biggest reasons for the simpler interventions not to help with GORD is that they are not given enough time to make a difference. Having said that, if a tired parent is repeatedly confronted with a grizzly, uncomfortable baby who is refusing to feed, asking them to persevere for two weeks with an intervention they don’t think is helping, may be practically difficult to achieve.
In the UK, we have a choice of two key guidelines to help us with the next steps in reflux management.
- NICE, last updated 2019
OR
- ESPGHAN/NASPGHAN 2018 joint consensus guidelines which are endorsed and recommended by our own BSPGHAN
- European Society of Paediatric Gastroenterology, Hepatology and Nutrition
- North American Society of Paediatric Gastroenterology, Hepatology and Nutrition
- British Society of Paediatric Gastroenterology, Hepatology and Nutrition
Except that these guidelines differ a little on the advice they give for when simple measures don’t help…
NICE recommend a trial of Gaviscon first, and if that doesn’t work 4-8 weeks of a PPI such as omeprazole, and only then suggest a trial of cow’s milk protein exclusion (either through use of a hydrolysed formula or maternal dairy exclusion in breastfed infants) as a last resort, if reflux does not improve after ‘optimal medical management’.
NASPGHAN/ESPGHAN on the other hand, suggest that ALL infants undergo an initial trial of cow’s milk protein exclusion, and only if this fails do they suggest the use of a PPI or hydrogen receptor antagonist (H2RA) such as Ranitidine. The bottom line is, that no-one has looked at the efficacy of a cow’s milk protein-free diet for symptom relief in babies presenting with reflux as the single symptom of cow’s milk protein intolerance (CMPI).
The NASPGHAN team argues, that whilst there is no evidence on the topic, there are a number of babies with CMPI manifesting as reflux only who will benefit from this approach. They suggest eliminating cow’s milk protein from an infant’s diet for a minimum of 2 weeks, ideally four. If symptoms resolve and reappear on reintroduction then the diagnosis is clear.
NASPGHAN then suggest babies who do not respond should be referred to secondary care services and started on a time-limited trial of PPI.
This is largely so that infants are not left struggling on inadequate therapy for long periods of time, but also because their review found conflicting evidence around the benefit and side effect profile of these medications for young children.
In six studies looking at PPI versus placebo, four studies showed no difference in regurgitation or other reflux associated symptoms between intervention and control groups. Three studies comparing H2RAs to placebo did show some benefit of the intervention, however, these studies were all in older children with biopsy-proven erosive oesophagitis up to 8 years of age. Two studies showed endoscopic and histological and clinical features of GORD were reduced with H2RA over placebo, but these were in mixed-age groups including children up to 8 years old.
All studies showed a similar profile of side effects and between drug and placebo arms, however, one study demonstrated an increased rate of infection, in particular lower respiratory tract infection and diarrhoea in the PPI group.
Given these findings, NASPGHAN cautiously recommends PPI or H2RA therapy in babies who have troublesome reflux despite trying a number of other non-pharmacological management options.
Their key message is around early referral to secondary care, giving sufficient time for any one intervention to work, and making sure children are appropriately followed up.
So, what should I do?
Given the somewhat conflicting advice outlined by these two well-respected groups, you could be left feeling unsure how to manage your next case. However, the genuine gap in the evidence market here does mean you are free to exercise your own clinical judgment and tailor your decision making to each individual refluxy baby, whilst empathetically taking on board the thoughts and preferences of the family. This could, for some babies and parents, be medicine in itself.
And what about alginates?
Two studies in the large literature review by the NASPGHAN/ESPAGHN group, compare Gavsicon to placebo. They show a reduction in visible regurgitation but no difference in reflux-associated symptoms. Furthermore, infants treated with alginate and then undergoing pH MII for 24 hours, showed no difference in the frequency of regurgitation events between groups.
Chronic use of alginates causes constipation and poses a theoretical risk of milk-alkali syndrome, which is perhaps why the authors suggest use is limited to short term therapy. NICE do recommend a trial of Gaviscon therapy at an early stage in their pathway, as an alternative to feed thickener, but again on a time-limited basis with a planned review.
Isobel’s mother had already tried two weeks of feed thickener on recommendation from the GP with no improvement. She was keen to avoid medication if possible so you agreed to a trial of dietary cow’s milk elimination for Mum who would continue to breastfeed and give top-ups with a hydrolysed formula if there was still no weight gain in a week. You gave her a sheet of dietary advice to ensure she maintained her own calcium intake and asked her to see the GP in 2 weeks for a review.
Take home message
- The vomiting infant has a wide differential – actively look for red flag features and investigate if you are concerned.
- Infants with GORD need a management plan; infants with GOR, leave well alone
- Start simply with an intervention that the family are happy to trial
- Give time for it to work (up to two weeks)
- Ensure follow-up for all and onward referral for infants who require acid-suppressive medication
References
- Loots et al. Body positioning and medical therapy for infantile gastroesophageal reflux symptoms. Journal of Pediatric Gastroenterology and Nutrition 2014; 59 (2): 237-243.
- Rosen et al. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition. JPGN 2018; 66(3): 516-554.
- Winter et al. Efficacy and safety of pantoprazole delayed release granules for oral suspension in a placebo-controlled treatment withdrawal study in infants 1-11 months old with symptomatic GERD. JPGN 2010; 50: 609-618.
- Orenstein et al. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. Journal of Pediatrics 2009; 154: 514-520e4.
- Davidson et al. Efficacy and safety of once daily omeprazole for the treatment of gastroesophageal reflux disease in neonatal patients. Journal of Pediatrics 2013; 163: 692-698.e1-2.
- Winter et al. Esomeprazole for the treatment of GERD in infants ages 1-11 months. JPGN 2012; 55: 14-20.
- Hussain et al. Safety and efficacy of delayed release rabeprazole in 1-11 month old infants with symptomatic GERD. JPGN 2014; 58: 226-236.
- Moore et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. Journal of Pediatrics 2003; 143: 219-223.
- Cucchiara et al. Cimetidine treatment of reflux oesophagitis in children: an Italian multi-centric study. JPGN 1989; 8: 150-156.
- Orenstein et al. Ranitidine, 75mg, over the counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux. Alimentary Pharmacology and Therapeutics 2002; 16: 899-907.
- Simeone et al. Treatment of childhood peptic esophagitis: a double-blind placebo-controlled trial of nizatidine. JPGN 1997; 25: 51-55.
- Miller et al. Comparison of the efficacy and safety of a new aluminium free paediatric alginate preparation and placebo in infants with recurrent gastroesophageal reflux. Current Medicines and Research Opinion 1999; 15: 160-168.
- Ummarino et al. Effect of magnesium alginate plus simethicone on gastro-oesophageal reflux in infants. JPGN 2015; 60: 230-235.
Gastroenteritis
Angharad Griffiths. Gastroenteritis, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.28790
Conor is a 10 kg, 13 month-old boy who’s presented to the ED with a 24-hour history of diarrhoea and vomiting. He has had 5 episodes of non-bloody, non-bilious vomits. Since waking up this morning has two episodes of loose/watery non-bloody malodorous stools. They have not ‘flooded’ the nappy but were quite large. He is taking sips of fluid (mixtures of water, milk, and juice being offered) and has only eaten half a digestive biscuit so far today. He has had a fairly large wet nappy last night, but not since, though it’s now difficult to tell as his last nappy was dirty. He is alert and looking around while being carried but is upset on leaving his mother’s arms. He cries with tears, has a normal heart rate but his mother is worried about his dry lips. She was told by a healthcare worker neighbour that he will “need a drip”. CRT, HR, and BP are normal. His temperature is 37.8. His nappy is dry and has been on for 3 hours now. His capillary glucose measurement is 3.2. You decide he’s probably mildly dehydrated.
Introduction
Gastroenteritis (GE) is the presence or diarrhoea or vomiting (or both) that may or may not be accompanied by fever, abdominal pain and anorexia. Diarrhoea is the passage of excessively liquidy or frequent stools with liquid high water content. Although often felt to be a common minor illness presentation, it is a major cause of childhood mortality and morbidity, causing millions of deaths worldwide in children in low and middle-income countries; of all child deaths from gastroenteritis 78% occur in Africa and South-East Asia.
Gastroenteritis accounts for a huge proportion of GP and ED presentations. In Europe, acute gastroenteritis the third commonest cause of hospital admission, accounting for between 4-17% of admissions. In Australia, gastroenteritis caused by rotavirus alone accounts for 115,000 GP visits, 22,000 ED visits and 10,000 hospital admissions a year, with an estimated cost of 30m Australian Dollars (£12m, €18m). In the UK, 20% of GP consultations in the under 5’s are for GE.
It is imperative that the child with gastroenteritis is differentiated from more sinister causes of vomiting. The presence of diarrhoea is reassuring but doesn’t exclude other intra-abdominal causes. The same can be said for pain out of proportion with gastroenteritis, distension, peritoneal signs or localised tenderness.
Most cases are not associated with complications but when complications do occur, the commonest are electrolyte disturbance and metabolic acidosis. Supplementary fluids through oral or intravenous routes are the most effective way to avoid these complications.
Gastroenteritis in low and middle-income countries can present differently, has different aetiologies, is often managed differently, and is a larger burden to healthcare systems in general than in high-income countries. This post will focus on gastroenteritis in high-income countries. For more information about comparisons of guidelines across the world; Vecchio et al (2016) is an interesting read.
This is not meant to provide a clinical practice guideline; rather an overview of the illness. Many (if not all!) paediatric emergency departments or general paediatric units have their own guidelines.
Pathophysiology
Worldwide, the commonest causes are viral pathogens, most commonly rotaviruses and noroviruses. Viral infections cause damage to the small bowel enterocytes with resultant low-grade fevers and watery diarrhoea – classically without blood. Rotavirus strains are seasonal and vary within different geographical areas. The peak age for these infections is between 6 months and 2 years. Children with poor nutrition are at higher risk of acquiring gastroenteritis and developing dehydration and complications.
Children with bacterial gastroenteritis are more likely to have bloody stool.
Escherichia coli and Shigella dysenteriae can be complicated by haemolytic uraemic syndrome (HUS). This is an acute onset, microangiopathic haemolytic anaemia, thrombocytopaenia, acute renal impairment and multisystem involvement. (Just to confuse things, HUS can present in the absence of bloody diarrhoea.)
Pathogens can be generalised into four groups:
Transmission
Pathogens are spread mainly via the faeco-oral route, acquired by ingesting contaminated food or drink. Water may be contaminated with bacteria, viruses, or protozoa. Undercooked (or inappropriately stored/cooked) meats and seafood are common culprits of bacterial pathogens. Bacterial contaminants can produce toxins (e.g. Bacillus cereus in re-warmed rice or Staphylococcus aureus in ice-cream).
Pathogens causing gastroenteritis can also be transmitted without the patient being symptomatic.
Assessment
Gastroenteritis is a clinical diagnosis. Enquire about sick/infectious contacts and potential sources (recent travel, food). Enquire about the frequency of symptoms and intake of fluids. Note the frequency of urination. Note other things that may cause diarrhoea e.g. recent use of enteral antibiotics or chronic constipation with overflow diarrhoea the presenting feature.
In the presence of signs such as high fever, long duration of symptoms, severe abdominal pain or bilious vomiting; review the diagnosis and do not immediately label as gastroenteritis.
Oral hydration fluids
Most children are not dehydrated and can tolerate oral fluids and so can be managed at home. Take a look at Nikki Abela’s DFTB19 talk on top tips for a high yield dehydration assessment.
When children are only mildly to moderately dehydrated, as a general rule they can be treated with oral / enteral rehydration with low osmolality oral rehydration solution (ORS). Worldwide, ORS is recognised as first line therapy and treating mild to moderate dehydration with enteral rehydration is supported by the WHO, European Society for Paediatric Gastroenterology and the American Academy of Paediatrics. The WHO recommends a low osmolality (hypo-osmolar) solution, usually containing sodium, potassium, chloride, carbohydrate (glucose) and a base. Low osmolarity solutions reduce the need for IV fluids, reduce stool output and reduce vomiting frequency.
But… a major limitation to the use of ORS is its taste – and this is where apple juice comes in. For minimally dehydrated patients, half-strength apple juice is associated with fewer treatment failures compared to ORS and could suit as a more palatable alternative. Take a look at a sweet summary (pun intended!) of the “apple juice trial”.
Breastfeeding should continue and a child can be supplemented with ORS if this is needed. Children can go back to a normal diet after the illness has passed.
Enteral (oral / NG) versus IV hydration
Most studies show that enteral rehydration with ORS is just as effective as IV hydration in mild to moderate dehydration with a 2006 Cochrane analysis concluding that enteral rehydration is as effective if not better than IV rehydration with fewer adverse events and a shorter hospital stay. It is also less invasive (even with NG placement) and anecdotally satisfaction is greater amongst parents. It is very safe.
Enteral rehydration only fails in approximately 1 in 20-25 children.
Barriers to oral rehydration include unfamiliarity with the benefits, misconception that it takes longer than IV therapy, and that it has a high failure rate.
Contraindications to enteral rehydration include haemodynamic instability, abdominal distension, concern over ileus, absent bowel sounds, or impaired airway reflexes.
IV therapy is more invasive and involves placing and maintaining IV access. There are also iatrogenic complications including electrolyte disturbance should inappropriate fluids / composition / volume / rate be used.
But… in severely dehydrated children, put away the ORS and apple juice. They will need IV rehydration as first line.
Antiemetics
How can we support enteral fluids? Well, children who receive Ondansetron are less likely to vomit, have greater oral intake and are less likely to require IV hydration. A Cochrane review demonstrates that Ondansetron also increases the proportion of children who stop vomiting when compared to placebo [RR1.4] and reduces the proportion of children needing IV therapy (and therefore admission rate) [RR 0.41]. Median length of stay is also shorter in the ED.
Reported side effects are rare with very few reported side effects other than a few cases of increased frequency of diarrhoea.
Antiemetics alleviate vomiting by acting on the ChemoReceptor Trigger Zone and vomiting centre. Ondansetron is a 5HT3 receptor antagonist. This class of antiemetics have fewer adverse effects (than dopamine antagonists, anticholinergics, antihistamines and corticosteroids) and can be safely used in children. The NICE guideline discusses its off-licence use (at time of publication it’s licence was for post-operative nausea and vomiting and chemotherapy induced vomiting).
Ondansetron prolongs the QT interval. Recommendations are it should be avoided in those with long QT and should be used in caution where there may be electrolyte imbalance (severe dehydration) or on other QT-prolonging medication.
Ondansetron is relatively cheap £1.71 for 10 4mg tablets and is available in oro-dispersible form (though these are much more expensive at £36 for 10x4mg tablets) and liquid (£36.82 for 40mg [50ml] bottle).
Probiotics
An ESPGHAN working group position paper on the use of probiotics in acute paediatric gastroenteritis concludes that:
…the jury’s still out.
Other therapies
Antibiotics and anti-diarrhoeal agents aren’t routinely recommended in the management of paediatric gastroenteritis.
For gastroenteritis in high income countries, the WHO does not recommend adding zinc to a treatment regimen (it is for gastroenteritis in low and middle income countries).
Investigations
Routine lab testing in mild and moderate gastroenteritis is of little value in these patients and should be avoided unless clinically indicated.
This goes for stool samples too. Stool cultures are not routinely indicated in immunocompetent children with non-bloody diarrhoea.
Confirmation of viral gastroenteritis after the child has been discharged from the ED, and likely on the road to recovery at home, adds very little to (A) the clinical diagnosis of viral gastroenteritis in the ED, (B) the management plan and (C) the clinical outcome.
Should the investigation influence management, then stool sampling may be of benefit. This could be applicable where an outbreak may be suspected in school or creche, where there may be a public health benefit.
Stool samples should be sent in cases of bloody diarrhoea, immunodeficiency and recent foreign travel.
How about tests for dehydration? Sadly there is no one test that correlates clinically with dehydration. Urine specific gravity in infants is unreliable because the kidney reaches adult concentrating abilities after the age of 1. Also, the child often doesn’t begin urinating until rehydration has begun.
And glucose? Well, almost 10% of GE patients aged 1 month to 5 years in high income countries present with hypoglycaemia. Risk factors for hypoglycaemia on presentation include a longer duration of vomiting and increased frequency of vomiting. It would be reasonable to consider point of care glucose testing at triage for young children as identifying hypoglycaemia on clinical ground alone is difficult in this age group.
Prevention
The key to reducing the burden (and generally for an all-round happier life!) is in the prevention of acute gastroenteritis. Rotavirus vaccination is now commonplace thought the antibodies, the UK & Ireland and other countries around the world. It is very effective.
In the home and in the ED…Handwashing, handwashing, handwashing!
Vaccination leads to a profound reduction in presentations and admissions and a fall in overall seasonal workload, often within the first year after the introduction of universal vaccination against rotavirus. Even though only those under 1 year old are generally vaccinated, it has been shown to contribute to a significant herd effect with fewer cases than expected in older children. In Scotland, where initial vaccine uptake was 93- 94% during the first 2 years, annual rotavirus confirmed gastroenteritis cases fell by 84.7%, bed days reduced by 91% (from 325 to just 29), without any documented cases of intussusception. Reductions were seen across all age groups despite only infants receiving the vaccine. Similar results can be seen in other areas of the UK and Ireland.
The not to miss bits
But what happened to Conor?
Conor was given a cup of Dioralyte ORS and his favourite beaker filled with Dioralyte. His mum was encouraged to give him syringes of 5 mls of Dioralyte frequently or for him to take sips from his beaker and was asked to document on a piece of paper how many he received. He vomited after 30 minutes of this therapy.
You give him a dose of Ondansetron and place an NG tube and give him 100mls (10ml/kg) over 1 hour after deciding he does not need rapid rehydration but slightly more than normal maintenance. He then receives maintenance volumes of Dioralyte via his NG, which he tolerates well and then starts to take his own sips from his beaker.
He does not vomit in the ED again, has one episode of loose stools, passes urine, and is tolerating fluids orally. He’s smiling at you! You feel he can be discharged and council his mum regarding regular fluid intake, choice of fluids, of any red flags, and encouraged to return in the event of any concern.
Conor’s Dad calls to say that Conor’s 3 year old sister at home is now vomiting too! But it’s OK – He’s not too worried about her and Conor’s Mum has advised his Dad to start giving her regular sips of Dioralyte at home…
References
Colletti JE, Brown KM, Sharieff GQ, Barata IA, Ishimine P. The Management of Children with Gastroenteritis and Dehydration in the Emergency Department. J Emerg Med [Internet]. 2010;38(5):686–98. Available from: https://dx.doi.org/10.1016/j.jemermed.2008.06.015
Elliott EJ. Acute gastroenteritis in children. Br Med J. 2007;334(7583):35–40.
Vecchio A Lo, Dias A, Berkley JA, Boey C, Cohen MB, Cruchet S, et al. Comparison of Recommendations in Clinical Practice Guidelines for Acute Gastroenteritis in Children. Gastroenterology. 2016;63(2):226–35.
Freedman SB, Willan AR, Boutis K, Schuh S. Effect of dilute apple juice and preferred fluids vs electrolyte maintenance solution on treatment failure among children with mild gastroenteritis: A randomized clinical trial. JAMA – J Am Med Assoc. 2016;315(18):1966–74.
BK F, A H, JC C. Enteral vs Intravenous regydration therapy for children with gastroenteritis: A meta-analysis of randomized controlled trials. Arch Paediatr Adolesc. 2004;158(1):483–90.
Hartling L, Bellemare S, Wiebe N, Kf R, Tp K, Wr C, et al. Oral versus intravenous rehydration for treating dehydration due to gastroenteritis in children (Review). 2006;
Fedorowicz Z, Jagannath V, Carter B. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. [Internet]. Cochrane database of systematic reviews. 2011. Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005506.pub5/full
NICE. Management of vomiting omiting in children and y young oung people with gastroenteritis : ondansetron. NICE GUIDELINES. 2014. p. 1–20.
Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, Shamir R, et al. Use of Probiotics for Management of Acute Gastroenteritis : A Position Paper by the ESPGHAN Working Group for Probiotics and Prebiotics. 2014;58(4):531–9.
Forrest R, Jones L, Willocks L, Hardie A, Templeton K. Impact of the introduction of rotavirus vaccination on paediatric hospital admissions , Lothian , Scotland : a retrospective observational study. 2017;323–7.
MARLOW RD, MUIR P, VIPOND I, TROTTER CL FA. Assessing the impacts from the first year of rotavirus vaccination in the UK. Arch Dis Child. 2015;100(Supl 3):A30.