Isobel is a 10-week-old, exclusively breastfed, 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. Her parents ask if she has gastro-oesophageal reflux disease (GORD).
Gastro-oesophageal reflux and gastro-oesophageal reflux disease aren’t the same things
Gastro-oesophageal reflux (GOR) is when gastric contents move from the stomach to the oesophagus. This most commonly happens after feeds and in people of all ages.
It becomes gastro-oesophageal reflux disease (GORD) when that process causes symptoms (e.g. pain) that require some medical treatment. This is a subjective assessment, and there is no clear-cut clinical diagnosis.
Patients often mention silent reflux (or occult reflux), where gastric contents move to the oesophagus but do not go up to the mouth. As a result, there may be no noticeable regurgitation or vomiting.
How does the body limit gastro-oesophageal reflux?
The first line of defence against gastro-oesophageal reflux disease is the lower oesophagal sphincter (LOS), and the diaphragmatic pinchcock and angle of His which physically limits the frequency and volume of gastric contents refluxing into the oesophagus.
The second defence is oesophagal clearance when gravity and peristalsis remove the contents from the oesophagus and secretions serve to neutralise the acid.
The third defence is the oesophagal mucosal defence against luminal acid.
How does the lower oesophageal sphincter work?
The LOS is an extension of the circular muscles of the oesophagus. The anti-reflux barrier consists of the LOS and the crural portion of the diaphragm. The esophagogastric angle (or the angle of His) is the angle between the oesophagus and the greater curvature of the stomach and is normally acute. It is a functional barrier, and its intraluminal pressure is greater than that of the stomach and oesophagus. In adults, it is 3-6 cm long and has a pressure of 20 mmHg. (range 10-40 mmHg). An absolute pressure of <6 mmHg is required for GER. In infants, the length is only a few millimetres. The LOS relaxes 2.5 seconds after the initiation of a swallow and remains open during 10-12 secs until the food bolus passes through. Sphincter pressure decreases postprandially and is also decreased by among others: the presence of fat in the duodenum, progesterone, cholecystokinin, glucagon, estrogen, nitric oxide, dopamine, nicotine, alcohol, mint and chocolate.
Most physiologic reflux episodes occur in relation to Transient LOS Relaxations (TLESRs) or when sphincter tone adapts inadequately to changes in intra-abdominal pressure. TLOSRs are induced by gastric distension and incomplete swallowing (normal mechanism for burping and belching). The larger the meal the more TLOSRs, and the more reflux episodes! Higher intragastric osmolarity and greater gastric secretory volume also contribute towards more TLOSRs which may contribute to the efficacy of proton pump inhibitors and H2 receptor antagonists in decreasing secretory gastric volume and reducing TLOSRs.
The angle of His is usually acute. When the angle is obtuse, such as in hiatus hernias, this favours gastro-oesophageal reflux disease.
How does oesophagal clearance help?
This is influenced by peristaltic waves, gravity and saliva. Swallowed saliva contributes towards neutralising the pH of the refluxed acid. Swallowing itself stimulates antegrade peristalsis which clears the oesophagal contents.
Oesophagal mucosal resistance against injury to acid consists of:
- Pre-epithelial: mucous layer, surface bicarbonate ion concentration, unstirred water layer
- Epithelial defence: The oesophagus is lined by moist, partially keratinized stratified squamous epithelium. Tight junctions act as a barrier to molecules passing from the lumen to blood.
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.
- Physiological, due to low tone in the immature lower oesophageal sphincter
- Common, occurring in up to 50% of infants under 6 months
- 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 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 managing GORD, starting with non-pharmacological measures.
So, in the absence of red flag symptoms, do I need to prove it’s gastro-oesophageal reflux disease?
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.
Barium is out. Reliable biomarkers don’t yet exist. Scintigraphy, ultrasound and trial of a proton-pump inhibitor (PPI) are not useful in babies.
IF there are red flags then what investigations should we think about
Intraluminal pH monitoring measures the frequency and duration of acid oesophagal reflux episodes. A drop in intraesophageal pH <4.0 is considered an acid reflux episode.
pH monitoring has limitations because of its inability to detect non-acidic bolus movement into the oesophagus in particular in infants who are fed milk. This is problematic when evaluating reflux as a contributing factor towards respiratory disease in infants. Studies showed that in infants with apparent life-threatening events or apnea, 48% were nonacid. In a study of preterm infants with apnea, Magista et al found that 76% of reflux events were only weakly acidic (4
Multichannel intraluminal impedance (MII) detects GOR episodes based on changes in electrical resistance to the flow of an electrical current between 2 electrodes placed on the MII probe when a liquid, semisolid, or gas bolus moves between them. The combined pH and impedance monitoring are therefore able to detect reflux regardless of pH and provide symptom correlation with parental reports.
Upper GI endoscopy can also be performed to look for oesophagitis (macroscopic and histological changes) and gastritis. As this involves a general anaesthetic in children and has its own risks and complications, endoscopy is not usually a first-line investigation for simple suspected reflux disease.
OK, so I only need to investigate if I think there may be another cause for the symptom. How do I treat gastro-oesophageal reflux?
- 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, reflux-y 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 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
- 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 the 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 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 about 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 reflux-y 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 for gastro-oesophageal reflux disease?
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
- 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.
Excellent. Can we have more articles like this? Short and snappy but with lots of good information!