Key messages

• In children and adolescents with neurological impairment, we are very uncertain about the effect of adding an antireflux procedure (fundoplication) on symptoms of gastro-esophageal reflux, death, and major surgical complications (perforation or peritonitis), when compared to gastrostomy alone or gastro-jejunal tubes.

• The addition of an antireflux procedure when performing a gastrostomy may result in little to no difference in the number of hospitalizations for respiratory disease (pneumonia).

• Further research is necessary. Better designed observational studies could help to improve our confidence in the evidence.

Why treat gastro-esophageal reflux in children with neurological impairment?

Because of damage to their central nervous system, children with neurological impairment are prone to vomiting and feeding difficulties, and are at increased risk of dying from lower respiratory tract infections, such as pneumonia. The treatment of gastro-esophageal reflux (where the stomach acid frequently flows back into the esophagus [food pipe] and causes heartburn) aims to prevent these symptoms and complications.

How is gastro-esophageal reflux that doesn't get better with medicine treated in these children?

The two most common procedures used to treat or prevent the consequences of gastro-esophageal reflux (antireflux procedures) in children with neurological impairment are fundoplication, where the stomach is wrapped around the lower esophageal sphincter, and the placement of a gastro-jejunal tube, which passes a feeding tube from the stomach into the small intestine (jejunum). These procedures differ in their surgical risks: fundoplication is more complex, requires more anesthesia (sedation), and involves a longer recovery period. Gastro-jejunal tubes are easier to place but require continuous feeding, which may increase caregiving needs and reduce the quality of life of children and their families.

What did we want to find out?

We wanted to find out if a fundoplication or passing of a gastro-jejunal tube is better than a gastrostomy (feeding tube entered directly into the stomach) alone to improve symptoms of gastro-esophageal reflux and number of deaths.

We also wanted to know if fundoplication caused more major surgical complications, and if antireflux procedures could prevent respiratory morbidity (pneumonia) in the long term.

What did we do?

We searched for studies comparing the two antireflux procedures (fundoplication or gastro-jejunal tubes) versus gastrostomy alone or versus each other in children and adolescents with neurological impairment.

We compared and summarized the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found 11 studies involving a total of 3122 children with neurological impairment. The children were followed up for between 9 months and 12 years.

Main results

Gastrostomy plus fundoplication compared to gastrostomy alone for gastro-esophageal reflux

• We are very uncertain about the effect on symptoms of gastro-esophageal reflux (3 studies, 180 children), death (3 studies, 415 children), major surgical complications within the first 30 days after surgery (3 studies, 412 children), and emergency department visits after surgery (1 study, 130 children).

• Gastrostomy plus fundoplication may result in little to no difference in number of hospitalizations for respiratory disease (pneumonia) (1 study, 2054 children).

• No studies looked at child's quality of life for this comparison. Length of stay after surgery was reported but not compared for gastrostomy plus fundoplication versus gastrostomy alone.

Gastro-jejunal tubes compared to gastrostomy alone for gastro-esophageal reflux

• We are very uncertain about the effect on death (1 study, 50 children) and child's quality of life (1 study, 50 children).

• No studies looked at symptoms of gastro-esophageal reflux, major surgical complications, length of stay after surgery, number of hospitalizations for respiratory disease (pneumonia), or number of emergency department visits after surgery for this comparison.

Gastrostomy plus fundoplication compared to gastro-jejunal tubes for gastro-esophageal reflux

• We are very uncertain about the effect on symptoms of gastro-esophageal reflux (3 studies, 1531 children), death (3 studies, 418 children), and major surgical complications during the first 30 days after surgery (2 studies, 190 children).

• Gastrostomy plus fundoplication may result in little to no difference in number of hospitalizations for respiratory disease (pneumonia) (1 study, 228 children).

• No studies looked at number of emergency department visits after surgery or child's quality of life for this comparison. Length of stay after surgery was reported but not compared for gastrostomy plus fundoplication versus gastro-jejunal tubes.

What are the limitations of the evidence?

We have little to very low confidence in the evidence. There were many problems with the methods of the included studies, such as incomplete reporting, differences among the participants in each group, and small study sizes that prevented the recording of events that don't occur very often during the follow-up period. Also, the included studies did not report all the outcomes we were interested in.

How up-to-date is this evidence?

The evidence is current to September 2024.

Key words: neurological impairment, children, adolescents, gastrostomy, tubes, fundoplication, gastro-jejunal, gastro-esophageal reflux disease, gastro-oesophageal reflux, GERD.

Key messages

• A common treatment for inflammatory arthritis is a medicine that alters the immune system and so reduces inflammation (DMARDs). Stopping DMARD treatment around the time of surgery to treat an affected joint may increase people's risk of experiencing a flare (worsening symptoms), but may make no difference to their likelihood of developing an infection or experiencing an unwanted event after the operation.

• More studies are needed to assess the effects of stopping or continuing DMARDs on disease activity, function, and quality of life.

What is inflammatory arthritis?

Inflammatory arthritis (including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis) is a chronic (persistent) condition that causes abnormal inflammation in the joints, ligaments (connective tissue), and tendons (which attach muscle to bone), resulting in pain, stiffness, swelling, and loss of function. It is a progressive disease that, if uncontrolled, may result in irreversible joint damage, significantly impaired function and quality of life, and inability to work.

How is inflammatory arthritis treated?

Inflammatory arthritis is treated with medicines called 'disease-modifying anti-rheumatic drugs' or 'DMARDs' that control the inflammation, thus reducing symptoms (pain, swelling, or stiffness) and preventing joint damage.

However, since DMARDs alter the immune system, they may also increase the risk of infection, including surgical site infections.

What did we want to find out?

We aimed to find out about the benefits and risks of stopping compared to continuing DMARDs around the time of surgery in people with inflammatory arthritis. We were interested in:

• flare (worsening symptoms or increased disease activity)

• infections after surgery

• infection in the artifical (prosthetic) joint

• disease activity score (from questionnaires)

• function (measured by questionnaire)

• unwanted events (such as wound problems or complications from surgery)

What did we do?

We searched for studies that investigated the effects of stopping or continuing DMARDs around the time of surgery. People in the studies had to be adults with inflammatory arthritis. They could be undergoing any type of surgery except for emergency or unplanned surgery.

We compared and summarised the results and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found three studies with 306 people. All had rheumatoid arthritis and had been taking conventional synthetic (man-made) DMARDs for more than 10 years. They were all undergoing planned orthopaedic surgery, that is, surgery on bones, joints and tendons. Their average age was 56 years, and 83% were women. Studies were conducted in France, the UK and Japan. One trial reported receiving funding from a foundation unrelated to commercial purposes and two studies did not report funding sources.

Main results

Compared with continuation of DMARDs during surgery:

• discontinuation may increase the risk of flare: 37% more people had a flare or worsening of the underlying disease activity when stopping DMARDs during surgery compared to those who continued with DMARDs (2 studies, 224 people). Out of 100 people who continued DMARDs, none reported a flare, compared to 37 out of 100 people who stopped DMARDs;

• discontinuation may have little or no effect on postoperative infections: 0% fewer people had postoperative infections when stopping DMARDs (3 studies, 306 people). Out of 100 people who continued DMARDs, 3 had postoperative infections compared to 3 out of 100 people who stopped with continuation of DMARDs.

• only one study (64 people) reported postoperative joint infections, with no infections in people who continued or stopped DMARDs.

• discontinuation may have little or no effect on total unwanted events, such as problems with the wound (3 studies, 306 people) or serious unwanted events, such as need for further surgery or procedures (2 studies, 242 people); 9% more people reported an unwanted event and 2% more people reported a serious unwanted event when stopping DMARDs.

What are the limitations of the evidence?

We have little confidence in the evidence because we found only three studies, and people in the studies were aware of which treatment they were getting. This may affect their reporting of disease flare, unwanted events and serious unwanted events, but it probably does not affect how they reported postoperative infections. None of the studies measured prosthetic joint infections, disease activity and function, so we don't know the effect of stopping DMARDs around the time of surgery on them. We only found studies on one type of DMARD.

How up to date is this evidence?

The evidence is up-to-date to 24 March 2025.

Editorial note: This is a living systematic review. We search for new evidence approximately yearly and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Key messages

• Cyclosporine A (CsA) eye drops, including Restasis, Cequa, and other newer versions, may improve some signs and symptoms of dry eye compared with their "vehicle" (inactive eye drops containing no CsA) or artificial tears. However, we have only moderate or low confidence in these results.

• People who used CsA eye drops were slightly more likely to stop treatment due to unwanted effects, but overall, few people withdrew from studies for this reason.

• We need higher-quality, longer-lasting studies that look at the benefits and harms of CsA eye drops in people with dry eye disease of varying seriousness.

What is dry eye disease?

The eye's surface is moist and covered with a thin film of tears. When problems arise with the tear film, people can develop a common condition known as dry eye disease. People with dry eye may have eye discomfort (such as a feeling of grittiness), burning sensations, light sensitivity, and blurred or fluctuating vision, which can affect driving and reading and lower their quality of life.

Some people develop dry eye disease because of another health condition or as a result of eye treatment, while in others, the cause is unknown. Many cases of dry eye are linked to health conditions that cause inflammation (swelling and irritation) in and around the eyes.

What are cyclosporine A (CsA) eye drops?

CsA eye drops are anti-inflammatory medicines that aim to reduce eye surface inflammation, improve tear production, and prevent eye surface damage. CsA eye drops come in different strengths, typically ranging from 0.05% (lower strength) to 2% (higher strength).

What did we want to find out?

We wanted to find out whether CsA eye drops work better than eye drops containing all the same ingredients except cyclosporine ('vehicle eye drops' or just 'vehicle'), artificial tears, or another type or strength of CsA to improve:

• dry eye symptoms;

• eye surface health;

• tear production;

• how well tears stay on the eye (tear film stability).

We also wanted to find out whether people using CsA eye drops were more likely to stop using them because of unwanted effects than those using vehicle, artificial tears, or CsA drops of a different type or strength.

What did we do?

We searched for studies comparing CsA eye drops with vehicle, artificial tears, or another CsA formulation or strength. We compared and summarized the results of these studies and rated our confidence in the evidence based on factors such as study methods and the number of people in the studies.

What did we find?

We found 58 studies involving 10,225 people with dry eye disease. China, South Korea, and the USA contributed 35 of the 58 studies (60%). Participants were typically around 53 years old. Women made up about 80% of participants overall, though proportions varied across studies from 46% to 100%. Pharmaceutical companies funded or sponsored nearly half of the studies. Non-profit organizations supported 10 studies, six studies had no external funding, and 14 studies did not report funding sources.

We grouped the studies into six groups based on CsA strength and the comparison treatments. Here, we focus on three groups with the most data.

Main results

Comparison 1

Compared to vehicle, artificial tears, or both, using CsA 0.05% eye drops for three months may have slightly improved people's:

• dry eye symptoms (13 studies, 1396 people);

• eye surface health (7 studies, 1355 people).

Results for tear production and tear film stability were inconsistent, preventing us from drawing firm conclusions.

Comparison 2

People using CsA eye drops of different strengths and types may have had slightly better tear production than those using CsA 0.05% eye drops after three months, but the difference between groups was small (5 studies, 572 people). We are uncertain about the effects on:

• dry eye symptoms;

• eye surface health;

• tear film stability.

Comparison 3

Compared to vehicle, artificial tears, or both, using CsA 0.1% eye drops for three months:

• probably improved eye surface health slightly (7 studies, 2940 people);

• may have improved tear production slightly (3 studies, 735 people).

Results for dry eye symptoms were inconsistent, preventing us from drawing firm conclusions. We are uncertain about the effect of CsA 0.1% on tear film stability.

Stopping treatment due to unwanted effects

Compared with people using vehicle eye drops or artificial tears, those using CsA 0.05% or 0.1% were slightly more likely to stop treatment due to unwanted effects. Overall, only a few people stopped treatment because of unwanted effects.

What are the limitations of the evidence?

We have little confidence in the evidence for dry eye symptoms, eye surface health, tear production, and tear film stability because study results were often inconsistent or too uncertain to determine the true size of the effect. Many studies gave unclear or few details about their methods. However, we are moderately confident in the evidence about stopping treatment.

How up to date is this evidence?

The evidence is current to March 2026.

Key messages

• Venepuncture (inserting a needle into a vein) may be less painful than heel lance (using a special device to puncture the skin) for newborn babies when having a blood sample taken, with or without sugar water for pain relief, and may reduce the need for more than one skin puncture when no sugar water is given for pain relief.

• We don’t know which procedure, venepuncture or heel lance, is more painful for newborn babies when sugar is used for pain relief.

• We need better designed and larger studies that fully report their results to show which method is better for babies.

Why do we take blood samples from newborn babies?

In most countries, a blood sample from newborn babies is needed for routine screening tests. Blood samples may also be needed for other blood tests to diagnose and manage diseases, such as jaundice or low blood sugar (hypoglycemia). However, taking blood from babies is painful. Untreated pain in newborn babies may affect their physical growth and brain development. A sweet, sugar solution (such as sucrose) can be given to babies before the procedure, which helps to reduce the pain. It is difficult to measure pain in babies, but we rely on things like facial expressions, crying, and changes in heart rate to assess their pain.

How are blood samples taken?Venepuncture

Venepuncture is a method of taking a blood sample where a person uses a needle to directly puncture the vein. The person who performs this must be well-trained to help ensure they successfully take a blood sample. This technique is often used when 1 mL or more of blood is required, and to prevent repeated punctures to the skin and associated complications (such as skin infections) from heel lance.

Heel lance

Heel lance is the standard way of taking a blood sample from newborn babies in hospitals worldwide. It is commonly used when the blood sample required is less than 1 mL. It does not require special training or expertise for successful use. The procedure involves making a small puncture (between 1 mm and 2 mm deep) on the heel of the foot using a lancet, which is usually an automatic device. Following the puncture, the infant's heel is squeezed to collect the required blood sample, which causes further pain.

What did we want to find out?

We wanted to find out:

• whether venepuncture is less painful than heel lance for newborn babies; and

• which procedure works best first time, so a second skin puncture is not needed.

What did we do?

We searched for studies that compared venepuncture and heel lance for taking blood samples in newborn babies. The studies needed to measure pain responses and the number of skin punctures needed for a successful sample. They also needed to record whether babies were given sugar solution as pain relief. Babies in the studies had to be healthy and born at full term. We compared and summarized the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We included eight studies involving 826 full-term newborn babies. Three studies took place in Sweden, and one each in Japan, Malaysia, Nepal, Spain, and the UK.

When no sweet-tasting solution was given:

• venepuncture probably causes less pain compared to heel lance (6 studies, 488 babies); and

• venepuncture probably reduces the need for more than one skin puncture compared to heel lance (6 studies, 397 babies).

When a sweet-tasting solution was given:

• venepuncture may cause less pain compared to heel lance (3 studies, 170 babies); and

• we are uncertain about the effect of venepuncture compared to heel lance on the need for more than one skin puncture (2 studies, 110 babies).

What are the limitations of the evidence?

Our confidence in the evidence was limited, and ranged from moderate to very low. This is because all the studies had limitations in how they were carried out. These included issues with how babies were assigned to each group, how the studies reported their results, and the number of babies included in the studies. In addition, the people doing the procedures knew which sampling method each baby received, which could have influenced how the studies assessed pain.

How up to date is this evidence?

This review updates our 2011 Cochrane review. The evidence is up to date to July 2025.

Key messages

• Most children with growth-plate pain (apophysitis) get better over time. Whether treatment for apophysitis affects short-term pain, physical function, and participation in sport is uncertain.

• It is uncertain whether any treatment is better or worse than any other. The studies were mostly small and had problems with their design. The studies did not always measure unwanted effects from a treatment, and none measured whether any children withdrew from studies because of unwanted effects.

• The evidence is limited. Most studies included more boys than girls, and included children who were more active than average. The children often knew which treatment they were receiving, which may have influenced the results.

What is apophysitis?

During puberty, children sometimes develop pain in the growth plates in their hips, knees, and feet. This pain is usually caused by irritation of the growth plate from repeated stress over time rather than from a single event. The pain is usually short-term and has limited impact on a child's life. However, sometimes the pain can make children limp, play less sport, or be less physically active. The conditions are called different names based on the location of the growth, but are commonly known as 'apophysitis' or 'lower limb apophyseal injuries'.

How is apophysitis treated?

Many different healthcare professionals treat apophysitis, including general practitioners or physicians, physiotherapists, and podiatrists. Many treatments are used, including exercises, medicines, strapping, braces, or devices put in shoes like foot orthoses or heel lifts. Regardless of treatment, apophysitis usually gets better on its own, but in some cases, the pain can last for a long time.

What did we want to find out?

We wanted to find out which treatments reduce pain effectively and to understand how safe these treatments are. We wanted to know which treatments improve how children function physically and take part in sport. We also wanted to know if one treatment worked better than another.

What did we do?

We searched for studies that tested the different types of treatments for apophysitis in the hip, knee, and foot. We did not search for any treatments that involved surgery.

We combined results from studies that tested the same treatments and used similar methods to measure effectiveness. We rated our level of certainty about this evidence.

What did we find?

We found 10 studies that involved 654 children whose average age ranged from 10.3 to 13.3 years. Seven studies focused on heel pain (calcaneal apophysitis), and three focused on pain in the front of the knee (traction apophysitis of the tibial tubercle).

Main results

• One study (23 children) compared a medicine called dexamethasone to a placebo (fake treatment). We are very uncertain whether dexamethasone reduces pain, improves physical function, or helps children return to sport in the short term. Two studies (74 children) reported unwanted effects of medicines, but the evidence was also very uncertain.

• One study (21 children) compared dexamethasone to usual care. We are very uncertain whether dexamethasone reduces pain, improves physical function, or helps children return to sport in the short term. One study (30 children) reported unwanted effects, but the evidence was also very uncertain.

• One study (22 children) compared Kinesio tape to a placebo. We are very uncertain whether Kinesio tape improves pain or physical function in the short term. The study did not report on participation in sport or unwanted effects.

• One study (124 children) compared foot orthoses to heel lifts. It found that there is probably little to no difference between them in terms of pain or physical function in the short term. The study did not report on participation in sport. One study (101 children) reported that there were no unwanted effects.

• One study (43 children) compared heel cushioning to a heel strap. We are very uncertain whether heel cushioning improves physical function or causes any unwanted effects in the short term. The study did not report on participation in sport.

• None of the studies reported whether any children withdrew from the studies because of unwanted effects.

What are the limitations of this research?

• In most studies, the children and carers knew which treatments they were receiving, which may have influenced how they reported improvements. This may affect how reliable the results are.

• Apophysitis often improves on its own as children continue to grow and the growth-plates close, so it is difficult to know if any improvements are due to treatments or natural recovery over time.

• There were many more boys than girls in the studies, and most participants were very physically active. It is unlikely that the condition impacts boys and girls differently, but we are unsure if our findings can be applied to children who are less physically active.

• Finally, most studies had only a small number of participants. This means we cannot be confident in the results and cannot know whether the findings would apply to a wider group of children with apophysitis.

How up to date is this evidence?

The evidence is current to 4 January 2025.

Key messages

- If damaged teeth are filled with a "bulk-fill" (material placed in one large layer) or a standard resin-based composite (RBC) material (placed in multiple layers), there is probably little or no difference in failure between the filling materials.

- Older evidence found that dental amalgam (silver-coloured fillings) may have fewer material failures than RBC. But this finding was based on older studies. Modern RBCs are better, dentists have more experience using them, and there are likely fewer failures.

Why do we need fillings and what are they?

Sometimes the tooth tissue becomes damaged, and holes (cavities) may form in the teeth. Cavities are caused by tooth decay, which is mainly a preventable disease if people adopt good oral hygiene and limit sugary foods and drinks.

When tooth decay leads to permanent damage, dentists may use a filling in the cavity to restore the tooth's shape and function.

What are the different materials used for fillings?

Traditionally, cavities were filled with amalgam. This silver-coloured filling material (made mainly from tin, silver and copper, and mixed with liquid mercury) is low cost and easy to use. But, it is now known that mercury can be harmful to people's health and the environment. At an international meeting, agreement was reached to reduce (or stop) the use of mercury, including in dental fillings. Alternative mercury-free filling materials that can be placed in a single dental appointment include:

- RBC: standard white or tooth-coloured material, applied in layers or in bulk.

- glass ionomer cement (GIC): sometimes used as a temporary filling, not as strong in some situations, so not suitable for chewing surfaces of teeth.

- resin-modified GIC (RMGIC): a hybrid GIC, stronger than GICs but not as strong as RBC.

- compomers: alternative to RMGIC but closer to composite than GICs.

RBC, RMGIC and compomers use an adhesive system to fix the material to the teeth, and need light-curing to harden the material. These are not needed with GIC.

What did we want to find out?

We wanted to find out:

- the benefits of one filling material compared to another for reducing tooth loss (because the filling has failed), failure (when the filling does not work as intended), length of time to failure, and tooth sensitivity after the procedure.

- whether one filling material is more cost-effective than another.

What did we do?

We searched for systematic reviews that looked at materials used for dental fillings in people's permanent back teeth. These reviews collect all the available evidence from published studies and analyse their results. We summarised the results of reviews alongside ratings of confidence (based on factors such as review or study methods and sizes) in the evidence that they reported.

We also looked for economic studies about the cost-effectiveness of these materials.

What did we find?

We found 14 reviews with 57 studies. The studies were undertaken between 1980 and 2023; one study had follow-up for 10 years but generally follow-up was much shorter. Some reviews did not report results for our critical outcomes, and sometimes the same studies were included in more than one review. We prioritised evidence from six reviews, with 25 unique studies.

We found seven studies about cost-effectiveness.

Main results

We found no reviews with evidence for tooth loss or length of time to failure.

- Although amalgam fillings may lead to fewer failures than RBC fillings (8 studies, 3486 fillings), the studies started in the late 1990s. RBCs, and dentists' experience using them, have improved since then. Failure with RBC is more likely to be 5% today (compared to 15% in the older studies). This means that older evidence comparing amalgam with RBC is less useful in modern settings.

- There is probably no difference between bulk-fill and standard RBC at reducing failures (7 studies, 511 fillings). It is likely that most people will experience no tooth sensitivity after either type of RBC material (5 studies, 510 fillings).

- There may be no difference between standard RBC and GIC at reducing failures (1 study, 60 fillings) or tooth sensitivity (4 studies, 311 fillings). RMGIC may be more likely to reduce failures than GIC (1 study, 50 or 38 fillings). We found reviews comparing GIC with amalgam and compomer, but these did not report failures or postoperative sensitivity.

- Most economic studies gave no overall conclusions about the cost-effectiveness of any of the materials. One economic study found that amalgam fillings were likely to last longer and be more cost-effective than RBC fillings, though this was based on an older study (from the late 1990s).

What are the limitations of the evidence?

Most reviews did not meet the highest standards. We judged only two reviews to be well-conducted. However, reviews mostly reported very similar results, even when they included different studies.

We were less confident in the evidence including GIC and RMGIC because studies were often small with few participants.

How current is this evidence?

The evidence is current to April 2025.

Key messages

• Live births are probably slightly decreased with recombinant follicle-stimulating hormone (rFSH) compared to purified (HMG) or highly purified (HP-HMG) human menopausal gonadotropin, but probably increased with rFSH compared to biosimilars (manufactured gonadotropins). There is probably little to no difference in live births between rFSH and purified follicle-stimulating hormone (FSH-HP) or follitropin delta. Clinical pregnancy is probably decreased with rFSH compared to HMG/HP-HMG but probably increased with rFSH compared to biosimilars. There is probably little to no difference in clinical pregnancy with rFSH compared with FSH-HP and follitropin delta.

• OHSS is probably higher with rFSH compared to HMG/HP-HMG and follitropin delta, but there is probably little to no difference with rFSH compared to FSH-HP, and there may be little or no difference with rFSH compared to biosimilars.

• Future research should focus on frozen embryos and cumulative outcomes across multiple frozen embryo transfer cycles to give a more complete picture of treatment effectiveness. Strategies for the prevention and management of OHSS should be prioritised.

What is in vitro fertilisation?

In vitro fertilisation (IVF) is a type of fertility treatment. Ovarian stimulation helps women’s ovaries produce more eggs, which are collected, fertilised and transferred back to the woman. Various hormones, including gonadotropins, are used to stimulate the ovaries:

• purified human menopausal gonadotropin (HMG) and highly purified (HP-HMG);

• purified follicle-stimulating hormone (FSH-P) or highly purified follicle-stimulating hormone (FSH-HP);

• recombinant follicle-stimulating hormone (rFSH) was developed in a laboratory to obtain higher purity of the hormone;

• follitropin delta was developed to work in a more personalised way; and

• 'biosimilars' are manufactured to offer similar results to rFSH at a potentially lower cost.

Ovarian hyperstimulation syndrome (OHSS) is an unwanted and sometimes serious effect of IVF, in which the ovaries swell and fluid can leak into the abdomen.

What did we want to find out?

We wanted to know which gonadotropin produced more live births, caused less OHSS, and led to more 'clinical' pregnancies, confirmed by ultrasound.

What did we do?

We searched for studies that compared one type of gonadotropin with another for women undergoing IVF. Studies could use fresh or frozen embryos.

What did we find?

We included 59 studies with a total of 18,119 women undergoing fertility treatment in a clinic.

rFSH versus HMG/HP-HMG (17 studies, 5639 women)

• Live births probably decrease with rFSH compared to HMG/HP-HMG. If the chance of live birth with HMG/HP-HMG is 28%, then the chance of live birth with rFSH is between 22% and 27%.

• OHSS is probably higher with rFSH compared to HMG/HP-HMG. If the risk of OHSS with HMG/HP-HMG is 2.6%, then the risk of OHSS with rFSH is between 2.9% and 4.7%.

• Clinical pregnancies probably decrease with rFSH compared to HMG/HP-HMG.

rFSH versus FSH-HP (23 studies, 4612 women)

• There is probably little to no difference in live births between rFSH and FSH-HP. If the chance of a live birth with FSH-HP is 27%, then the chance of a live birth with rFSH is between 24% and 31%.

• There is probably little to no difference in OHSS with rFSH compared to FSH-HP. If the risk of OHSS with FSH-HP is 2.5%, then the risk of OHSS with rFSH is between 1.7% and 3.8%.

• There is probably little to no difference in clinical pregnancy between rFSH and FSH-HP.

rFSH versus follitropin delta (7 studies, 3614 women)

• There is probably little or no difference in live births between rFSH and follitropin delta. If the chance of achieving a live birth with follitropin delta is 29%, the chance of a live birth with rFSH is between 24% and 30%.

• OHSS is probably higher with rFSH. If the risk of OHSS with follitropin delta is 4.4%, then the risk with rFSH is between 5.1% and 9.2%.

• There is probably little or no difference in clinical pregnancy between rFSH and follitropin delta.

rFSH versus biosimilars (8 studies, 2870 women)

• Live birth is probably higher with rFSH compared to biosimilars. If the chance of achieving a live birth with biosimilars is 23%, the chance of a live birth with rFSH is between 25% and 32%.

• There may be little or no difference in OHSS between rFSH and biosimilars. If the chance of OHSS with biosimilars is 9.6%, the chance of OHSS with rFSH is between 5.7% and 10%.

• Clinical pregnancy is probably higher with rFSH compared to biosimilars.

What are the limitations of the evidence?

The results mainly reflect IVF cycles with the transfer of a fresh embryo, so the results may be different for frozen embryos. Many studies were sponsored by pharmaceutical companies that manufacture the hormones in question, which could have affected the results. Furthermore, although we excluded some studies by using an integrity checklist, we have some concerns about the trustworthiness of the data from several of the studies.

How up to date is the evidence?

This updates a review previously published in 2011. The evidence is current to March 2025.

Key messages

• In adults who had treatment to reopen a blocked brain artery, lowering blood pressure very intensively (usually below 160 mmHg) does not improve the chances of living independently three months after the stroke compared with standard blood pressure targets (usually below about 180 mmHg). “Living independently” means being able to walk and manage most everyday activities without help.

• Intensive blood pressure lowering probably increases the risk of death and poor recovery after stroke. Differences in brain bleeding between intensive and standard blood pressure strategies were small.

• Most of the people in the studies were treated in hospitals in upper-middle and high-income countries with specialized stroke services. We do not know whether the results would be the same in countries with fewer resources or in all groups of people who have an ischemic (blood blockage) stroke.

What is an ischemic stroke?

A stroke occurs when the blood supply to part of the brain is suddenly interrupted. In an ischemic stroke, this interruption is caused by a blood clot blocking an artery in the brain. It can lead to various neurological problems, such as weakness, decreased sensitivity, lack of coordination, and difficulty speaking.

How is a stroke treated?

Doctors can sometimes reopen the blocked artery using clot-busting medicines given into a vein, or by performing a procedure to remove the clot with a thin tube passing through the blood vessels (often called mechanical thrombectomy). These are called reperfusion treatments because they restore blood flow to the brain.

After reperfusion, many people have very high blood pressure, which can increase the risk of bleeding in the brain. However, lowering blood pressure too much or too quickly can reduce blood flow to brain tissue that is still at risk and be harmful to the brain.

What did we want to find out?

We wanted to find out whether intensive blood pressure lowering after reperfusion treatment, compared with standard blood pressure control:

• improves recovery and ability to live independently;

• improves health-related quality of life;

• improves survival;

• increases or reduces bleeding in the brain;

• decreases the duration of days in hospital;

• affects the frequency of other unwanted effects.

What did we do?

We searched for clinical studies (in which people are assigned to groups by chance) that included adults with ischemic stroke who had received reperfusion treatment with a clot-busting medicine, mechanical thrombectomy, or both, and compared more intensive blood pressure targets (less than 160 mmHg) with standard targets (less than 180 mmHg) shortly after reperfusion.

We combined and summarized the results of the studies. We also considered how the studies were conducted, the number of participants included, and the similarities and differences between the studies to judge how much confidence we can have in the results.

What did we find?

We found nine studies, involving 4381 adults with ischemic stroke who had reperfusion treatment. Most participants were treated in hospitals in high-income countries, with a smaller number in hospitals in middle-income countries. None of the studies took place in low-income countries. In most studies, the intensive strategy aimed to keep systolic blood pressure (the top number in a blood pressure reading) below 140 mmHg, while the standard strategy aimed to keep it below about 180 mmHg.

Main results

• Intensive blood pressure lowering makes little or no difference to the chance of living independently about three months after the stroke, compared with standard blood pressure control.

• Intensive blood pressure lowering probably makes little or no difference to health-related quality of life.

• Differences in brain bleeding (including severe bleeding that worsens symptoms) between intensive and standard blood pressure strategies were small and uncertain.

• Intensive blood pressure lowering probably increases the risk of death and probably increases the chance of a poor recovery after stroke.

Overall, the results suggest that lowering blood pressure to very low levels after reperfusion is unlikely to provide additional benefit and might cause harm in some people, compared with keeping blood pressure within more standard targets.

What are the limitations of the evidence?

The evidence has several important limitations, such as the relatively small numbers of people in some studies, which reduce the reliability of the results. Additionally, most participants were treated in specialized centers in middle and high-income countries; there is no evidence from low-income countries. Some groups of people may be under-represented (for example, older adults with many other health problems), and many studies did not provide detailed results separately for women and men.

Because of these limitations, the results should be interpreted with caution. More research is needed to determine whether specific groups of people might benefit from different blood pressure targets.

How up to date is this evidence?

The evidence in this review is up to date as of March 2025.

Key messages

• Compared to placebo (a 'dummy' treatment with no active ingredient), weight-loss medicines may reduce body mass index (which measures whether someone's weight is in a healthy range) and weight slightly. Weight-loss medicines probably make little to no difference to the number of people experiencing unwanted or harmful events.

• We do not know if weight-loss medicines plus lifestyle changes are more effective than lifestyle changes alone, or whether they lead to any unwanted events.

• To better understand the benefits and risks, we need more studies that follow young people for at least one year and measure their physical and mental well-being.

What is obesity?

Obesity means having too much body fat. Obesity in children (0 to 9 years) and adolescents (10 to 19 years) increases the risk of several diseases in the short term and adulthood. Obesity also affects how young people feel about themselves and interact with others, often resulting in low self-esteem, anxiety, depression, and social difficulties.

How is obesity treated?

Obesity is a complex problem with many factors. Children and adolescents with obesity may benefit from lifestyle changes, such as improvements in diet and exercise, counseling, and behavioral support. Weight-loss medicines are typically only considered when lifestyle changes have not worked.

Several medicines are used for obesity in children and adolescents, including newer medicines called GLP-1 agonists, better known by brand names such as Wegovy and Ozempic. We considered the effects of all weight-loss medicines together.

What did we want to find out?

We wanted to learn if weight-loss medicines are better than a placebo (a 'dummy' treatment with no active ingredient) or lifestyle changes at:

• reducing body mass index (BMI) — a number calculated from a person's weight and height that indicates whether their weight is in a healthy range, expressed as kilograms per meter squared (kg/m2);

• reducing weight (kg);

• improving well-being.

We also wanted to find out if these medicines lead to:

• unwanted events;

• people leaving the studies early due to unwanted events;

• obesity-related health problems, including high blood sugar, high blood pressure, and unhealthy blood fat levels.

What did we do?

We searched for studies that compared weight-loss medicines with placebo, no treatment, another weight-loss medicine, or lifestyle changes in children and adolescents, and lasted at least three months. We compared and summarized the results of the studies and rated our confidence in the evidence based on factors such as study methods and the number of young people involved.

What did we find?

We included 37 studies with 4218 young people. Twenty-eight studies involved adolescents only. Eight included children and adolescents. One study planned to include children as well as adolescents, but did not mention their ages. Thirty-one studies compared weight-loss medicines to placebo. Six compared weight-loss medicines plus lifestyle changes (changes to diet, physical activity, or both) to lifestyle changes alone.

Main results

Compared to placebo, weight-loss medicines:

• may reduce BMI by an average of 1.8 kg/m2, based on evidence from 25 studies with 3091 young people. This is a small reduction, and may not meaningfully improve young people's health;

• may reduce weight by an average of 5.47 kg (20 studies, 2380 people);

• probably make little to no difference to young people's well-being (4 studies, 741 people);

• probably make little to no difference to the number of people experiencing unwanted events, which was high in both groups: 872 of 1000 people given weight-loss medicines and 846 of 1000 given placebo experience unwanted events (8 studies, 1877 people);

• may make little to no difference to the number of people leaving studies early due to unwanted events: 36 people per 1000 given medicine leave early, compared to 24 people per 1000 given placebo (13 studies, 2213 people);

• may make little to no difference to obesity-related health problems (1 study, 51 people).

There are important differences in the reductions in BMI and weight for different weight-loss medicines.

We are very uncertain about the effects of weight-loss medicines plus lifestyle changes compared to lifestyle changes alone on:

• BMI change;

• weight change;

• the number of people leaving studies early due to unwanted events.

No studies in this comparison measured young people's well-being, the number who experienced unwanted events, and obesity-related health problems.

What are the limitations of the evidence?

For both comparisons, our confidence in the evidence for most outcomes was reduced because the studies used methods likely to introduce errors in their results.

For weight-loss medicines versus placebo, our confidence in the evidence for BMI and weight was also reduced because the studies' results varied. We had little confidence in the evidence about the number of people who left studies early due to unwanted events because it was based on only a few cases. We had only moderate confidence in the evidence for well-being because there were too few studies to be certain about the results.

How up to date is this evidence?

The evidence is current to July 2023. In June 2025, we checked the status of ongoing studies, and updated the results accordingly.

Key messages

• Several medications can help rheumatoid arthritis symptoms after failure of a biologic or targeted synthetic (b/ts) disease‐modifying antirheumatic medicine (DMARD) (a type of medication that stops or slows the disease process).

• We are unsure how the medications compare with placebo (dummy treatment) or with each other in terms of unwanted effects.

• We need more studies that directly compare drugs to get a better idea of which is best. Treatment decisions should consider individual health factors and preferences.

What is rheumatoid arthritis?

Rheumatoid arthritis is a disease where the body’s immune system, which normally fights infections, mistakenly attacks the joints. This causes joint pain, swelling, stiffness, and disability. Rheumatoid arthritis is a long-term condition, but treatments can help manage symptoms and slow the damage.

How is rheumatoid arthritis treated?

Rheumatoid arthritis is typically treated with disease-modifying antirheumatic drugs (DMARDs), which work to control the inflammation responsible for symptoms and also prevent joint damage. There are various kinds of DMARDS. Targeted synthetic (ts) DMARDs work by targeting specific cells or proteins. Biologic (b) DMARDs also target specific cells or proteins, but are made from material that comes from living organisms. Lastly, conventional synthetic DMARDs affect the whole immune system rather than targeting specific parts of it.

What did we want to find out?

We wanted to explore the effectiveness of DMARDs in adults with rheumatoid arthritis for whom treatment with a b/ts DMARD didn't work. This is a 'living' systematic review, meaning that it will be updated regularly. As this field of medicine is always growing and changing, we want to have the most up-to-date evidence reflected in this review.

What did we do?

We searched for studies that tested the effectiveness of DMARDs in adults with rheumatoid arthritis for whom treatment with one b/ts DMARD didn't work.

We looked at how well the available DMARDs reduced the symptoms of rheumatoid arthritis, including pain, joint swelling, and issues with joint movement. We measured this using the American College of Rheumatology 50% response criteria, or ACR50 response. An ACR50 response means the rheumatoid arthritis medication is effective and symptoms have improved by at least half. We also looked at any unwanted effect that might cause a person to stop using the medication.

We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found 19 studies that involved 4779 people with rheumatoid arthritis who had tried a tumour necrosis factor inhibitor (a type of bDMARD) in the past, but it did not improve their symptoms. Most people in these studies were women, with an average age of 49 to 58 years, who had been living with rheumatoid arthritis for an average of 6 to 14 years. The studies were conducted worldwide, including in North America, Europe, and Asia. Nine studies were funded by pharmaceutical companies, while the other 10 were funded by national research grants.

Several medications reduced the symptoms of rheumatoid arthritis in patients who have failed a b/ts DMARD:

• a different tumour necrosis factor inhibitor (2 studies; 343 people);

• sarilumab (1 study, 365 people);

• tocilizumab 4 mg/kg (1 study, 319 people);

• tocilizumab 8 mg/kg (1 study, 328 people);

• intravenous (into a vein) abatacept (2 studies, 665 people);

• rituximab (1 study, 499 people);

• upadacitinib (1 study, 333 people);

• tofacitinib (1 study, 263 people);

• a higher dose of baricitinib (1 study, 353 people).

We are unsure how the medications compare with placebo (dummy treatment) or with each other in terms of unwanted effects, as the evidence for this outcome was generally of low quality.

What are the limitations of the evidence?

Our confidence in the evidence varied from high to very low. In cases where our confidence was limited, this was because there were not enough studies to be certain about the results. When we searched for studies to include in the review, we found some gaps in the available evidence. Specifically, we found that there were fewer studies that directly compared medications with each other and more studies that compared medications to a placebo. More studies that compare drugs directly would better help us understand which drug is best.

How up to date is this evidence?

The evidence is current to 28 November 2025. As this is a living review, we will be updating this research yearly to ensure our results reflect new evidence.

Key messages

• Compared to no physical activity, any type of physical activity may help children with obesity to reduce their BMI slightly (the 'body mass index' is used to check if someone is a healthy weight) and may lead to considerably more minor unwanted events, but we are very uncertain about these results.

• We do not know if physical activity has any effect on the weight, body fat percentage, well-being, and blood sugar levels of children with obesity compared to no physical activity or another type or amount of physical activity. We also do not know if physical activity has any effect on the number of serious unwanted effects.

• We need larger, longer-lasting, and better-quality studies to be more certain about the effects of physical activity on children with obesity.

What is obesity?

Obesity is when a person has too much body fat. Worldwide, obesity amongst children (aged 0 to 9 years) has increased substantially since 1975. More than 300 million children and adolescents (aged 10 to 19 years) may be living with obesity by 2050.

Children with obesity are more likely to develop health problems such as heart disease, stroke, type 2 diabetes, some cancers, liver disease, asthma, joint and muscle problems, and infections later in life. Childhood obesity is also linked to higher rates of anxiety and depression.

Weight loss is the best way to reduce the health risks caused by obesity. In children, this is usually done through lifestyle changes such as doing more physical activity (e.g. running games or interactive video games that encourage movement (sometimes called 'exergaming')) and eating healthier foods.

What did we want to find out?

We wanted to find out if, compared to no physical activity, physical activity helps children with obesity:

• reduce their BMI (the 'body mass index' indicates if someone is a healthy weight; their weight is divided by their height multiplied by itself, expressed as kg/m2) or BMI z-score (how someone's BMI compares to BMIs of others of the same age and sex);

• lose weight;

• improve their well-being;

• reduce body fat percentage or improve how body fat is distributed in the body; and

• lower their blood sugar levels.

We also wanted to find out if one type or amount of physical activity was better than another type or amount at producing these benefits, and if the physical activity programmes led to any unwanted effects.

What did we do?

We searched for studies that compared participating in physical activity to:

• no physical activity;

• another type or amount of physical activity.

The children needed to do the physical activities for at least 12 weeks. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and number of participants.

What did we find?

We found four studies including 517 children. The studies were small: the smallest included only 59 children and the largest, 222. Just under half of the children involved were girls (46%). Their average age was 9 years.

In three studies, the children did the physical activities for 12 or 13 weeks; the fourth study's physical activity programme lasted 32 weeks. The studies took place in three countries: one study each in Brazil and Iran, and two studies in the USA. In the American studies, 73% of the children were Black. The other studies did not describe the children's ethnicities.

• All four studies compared physical activity to no physical activity.

• One study also compared one type of physical activity (exergaming) to another type (swimming pool exercises).

• One study also compared doing 20 minutes versus 40 minutes of the same physical activities.

Main resultsPhysical activity versus no physical activity

Compared to no physical activity, children with obesity who participated in any physical activity programme may have:

• slightly reduced their BMI: the BMI of children in the active groups was on average 1.52 kg/m2 lower (2 studies, 118 children);

• experienced more minor unwanted effects: children in the active groups may have been about 3.5 times more likely to experience minor unwanted effects (1 study, 222 children).

However, we are very uncertain about these results.

We do not know if physical activity makes any difference to children's:

• BMI z-score;

• weight;

• well-being;

• body fat percentage or how fat is distributed in the body;

• blood sugar levels;

• risk of experiencing serious unwanted events.

One type or amount of physical activity versus another type or amount

We are very uncertain about the effect of one type or amount of physical activity compared with another type or amount on any of the points we were interested in.

What are the limitations of the evidence?

We have limited confidence in the evidence because:

• there were few studies and they were small;

• the types of physical activities varied;

• the studies' reporting of their methods and findings was poor;

• three out of four studies did not report all their results.

How up to date is this evidence?

This evidence is current to December 2025.

Key messages

• Medicines that help the body's immune system recognise and attack cancer cells can shrink the cancer and likely slow its return in people aged 65 years and older having surgery for the most common type of lung cancer. However, it probably does not increase how long people live overall.

• We do not have enough evidence yet to know if its benefits outweigh the harms, and no study assessed well-being.

What is resectable non-small cell lung cancer?

About 85% of people with lung cancer have what is called non-small cell lung cancer (NSCLC). It is most often found in older adults, with an average age at diagnosis of 71. When the cancer has not spread out of the lung, and if the person is fit enough to have surgery, the tumour can be removed. However, the cancer can come back after treatment, and between 30% and 55% of people eventually die from the disease. To reduce the risk of cancer coming back, different treatments can be used together.

How is resectable non-small cell lung cancer treated?

In recent years, lung cancer treatment has been transformed with the discovery of medicines that help the body's immune system recognise and attack cancer cells (immunotherapy). Immunotherapy works together with drugs that kill cancer cells (chemotherapy). When given before surgery, after surgery, or both, immunotherapy improves the chances of curing the cancer and helps delay its return.

What did we want to find out?

The ageing process affects the immune system, reducing its capacity to fight cancer: this is called immunosenescence. The elderly population is a very diverse group, and each person needs to be carefully assessed because age alone is not enough to base the best treatment decisions on. We wanted to find out if, despite immunosenescence, immunotherapy is effective in people aged 65 years and older, to cure lung cancer and prolong life without unwanted treatment effects.

What did we do?

We searched for high-quality studies that tested immunotherapy, either alone or in combination with chemotherapy, given before surgery, after surgery, or both, in people aged 65 and older. We summarised their results and assessed how confident we can be in the evidence, based on criteria such as how the studies were done and how many people were included.

What did we find?

For people aged 65 and older, we found results from 11 studies involving 3152 people with NSCLC. The studies compared immunotherapy alone or in combination with chemotherapy to a placebo (a sham or ‘dummy’ treatment) or no treatment, with or without chemotherapy. Treatments were given either only before surgery, only after surgery, or both before and after surgery.

Immunotherapy reduces the amount of cancer found at surgery and probably delays the cancer from coming back. Immunotherapy probably makes little or no difference to overall survival. There was not enough evidence to determine its effect on potential harms, and no study assessed well-being.

What are the limitations of the evidence?

Our confidence in most of the evidence is moderate because of some concerns about how the studies were conducted. More complete and longer-term data are needed to better estimate how much a person's lifespan might be extended. We have very limited confidence in the assessment of unwanted effects, because only one study provided data about these.

How up to date is this evidence?

The evidence is up to date to 3 July 2025.

Key messages

• Overall, we did not find sufficient evidence to show that medicines that block interleukin-1 (a protein involved in immune responses) are effective treatments for people with COVID-19, or whether they cause unwanted effects.

• We found 16 studies with unpublished results. We will update this review when new data are available.

• In future, we need high-quality studies to evaluate medicines that block interleukin-1 to treat COVID-19.

What is interleukin-1 and what is its role in COVID-19?

Interleukin-1 (IL-1) is a type of protein called a cytokine, which helps to regulate the body’s immune system. In particular, IL-1 triggers inflammation to help fight infection. In COVID-19, as the immune system fights the virus, the lungs and airways become inflamed, causing breathing difficulties. However, in some people, the immune system can over-react (called a ‘cytokine storm’) and produce dangerously high levels of inflammation and tissue damage. This can lead to severe breathing difficulties, organ failure and death.

What are interleukin-1 ‘blockers’?

IL-1 blockers are medicines that stop IL-1 from working by blocking signals from IL-1 to other parts of the immune system. This reduces inflammation and may help the immune system to fight COVID-19. In turn, this may reduce the need for breathing support with a ventilator (a machine that breathes for a patient) and reduce the number of deaths from COVID-19. Three IL-1 blockers are available: anakinra, canakinumab and rilonacept.

What did we want to find out?

We wanted to know if IL-1 blockers are effective treatments for people with COVID-19, compared with standard care alone or with placebo (a dummy treatment that appears identical to the medicine being tested but without any active medicine). We were particularly interested in the effects of IL-1 blockers on:

• whether people’s symptoms got better or worse;

• how many people died; and

• any unwanted effects and serious unwanted effects.

What did we do?

We searched for studies that assessed the effects of IL-1 blockers to treat people with COVID-19 compared with standard care alone or with placebo. People in the studies could have suspected or confirmed COVID-19 of any severity (mild, moderate or severe), and be any age or sex.

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found six studies with 2132 people. Four studies assessed anakinra (1633 people) and two assessed canakinumab (499 people). People in the studies were aged between 58 and 68 years old on average, and the majority were men. All the people in the studies were in hospital, mainly with moderate to critical COVID-19. The studies varied in size, from 45 to 2253 people. At the start of the studies, 67% to 100% of people were receiving oxygen, and 0% to 33% were on a ventilator.

We also found 16 studies that have not yet published their results.

Anakinra compared to usual care and placebo to treat people with COVID-19

• Anakinra probably results in little or no improvement in COVID-19 symptoms (defined as improvement on a clinical scale or discharge from hospital) at 28 days after treatment (three studies, 837 people) but we do not know if it makes a difference at 60 days (one study, 115 people).

• We do not know if anakinra makes a difference to the number of deaths at 28 days after treatment (two studies, 722 people) or at 60 days (four studies, 1633 people).

• Anakinra probably results in little or no increase in any unwanted effects at 28 days after treatment, but we are not sure about its effect on serious unwanted effects (two studies, 722 people).

Canakinumab compared to usual care and placebo to treat people with COVID-19

• Canakinumab probably results in little or no improvement in COVID-19 symptoms (defined as improvement on a clinical scale or discharge from hospital) at 28 days after treatment (two studies, 499 people).

• We do not know if canakinumab makes a difference to the number of deaths at 28 days after treatment (two studies, 499 people) or at 60 days (one study, 45 people).

• Canakinumab probably results in little or no increase in any unwanted effects (one study, 454 people), but we are not sure about its effect on serious unwanted effects (two studies, 499 people) at 28 days.

What are the limitations of the evidence?

Our confidence in the evidence is limited for several reasons. All the people in the studies were hospitalised, but some were more seriously ill than others - some studies only included people on a ventilator. Usual care also differed between studies, and studies measured and reported their results using different methods.

How up to date is this evidence?

The evidence is up to date to 5 November 2021.

Key messages

In people who have had previous rheumatic fever (the body attacking itself in response to bacterial infection) or have rheumatic heart disease (long-term damage to the heart due to rheumatic fever):

- long-term antibiotics (either injected into the muscle every month or taken as a tablet every day) probably reduce the risk of getting more episodes of rheumatic fever compared to no antibiotics;

- intramuscular antibiotics probably reduce the progression (getting worse) of early heart disease compared to no antibiotic; however, there is no evidence to compare intramuscular with oral antibiotics for progression of late-stage heart disease;

- antibiotics may not increase the risk of complications, such as a severe allergic reaction (anaphylaxis).

What is rheumatic heart disease?

Rheumatic heart disease is the top cause of heart disease in young people worldwide and kills about one-third of a million people every year. Rheumatic fever happens when the body's own defences go wrong, often because of a throat infection, fighting the heart instead of the bacteria. This can then lead to damage to the heart valves (gateways between rooms in the heart) called rheumatic heart disease. Antibiotics kill bacteria that can cause infections, reducing the risk of people developing rheumatic fever.

What did we want to find out?

We wanted to find out whether and, if so, how effective antibiotics are at reducing the chances of getting rheumatic fever again, and this leading to rheumatic heart disease.

What did we do?

We included studies that randomly gave people with past rheumatic fever or rheumatic heart disease antibiotics or not (e.g. based on flipping a coin). We were interested in comparing, firstly, long-term antibiotics with no antibiotics and, secondly, long-term intramuscular penicillin with long-term oral antibiotics. Participants in the studies we included had previous rheumatic fever or rheumatic heart disease, but could be any age. We looked for lots of different events that could have happened, including the rheumatic fever coming back (rheumatic fever recurrence), rheumatic heart disease getting worse (progression of rheumatic heart disease), problems with the heart (carditis), problems around pregnancy and birth (obstetric complications and foetal/neonatal events), death (mortality), whether people stuck to their treatment (treatment adherence), other problems such as dangerous breathing problems (anaphylaxis), complications such as nerve injury and whether the people included were happy with having antibiotics.

What did we find?

We found 11 studies (3951 participants) to help us answer our questions. People in these studies were an average of 12.3 years of age and were 50.6% male. Most had had previous episodes of rheumatic fever.

We found that using long-term antibiotics (either injected into the muscle every month or taken as a tablet every day) compared with no antibiotic probably reduces the risk of getting more episodes of rheumatic fever. The injection into a muscle route probably works better than the tablets. If you have the early stages of rheumatic heart disease picked up on an echocardiogram of the heart (a scan that uses sound waves to see the internal structure of the heart), then penicillin antibiotics injected into the muscle every month compared with no antibiotic likely reduces the risk of these heart problems getting worse. We found some evidence that antibiotics injected into the muscle compared with no antibiotics may not cause a very high risk of allergic reaction that affects breathing (anaphylaxis), but probably comes with a higher chance of redness at the injection side and allergic reactions to antibiotics. There was not much information on death rates or nerve injury, and no evidence on whether an antibiotic injection is better than tablets for preventing latent (early) rheumatic heart disease getting worse.

What are the limitations of the evidence?

The majority of the included studies (nine) were not carried out in low-income countries, which currently have the most cases of rheumatic heart disease. This makes these results potentially less relevant to people in these countries. There is also little information on important questions other than recurrence of rheumatic fever or progression of rheumatic heart disease. There were some other potential limitations in the evidence: we flagged six studies as having issues with blinding (study participants or staff knowing whether they received antibiotics and so potentially answering based on this information). It is possible that people in many of the included studies were aware of which treatment they were getting. Four studies may have had a problem with the process for placing people randomly into groups. For some of the results in the review, we only had one study.

More high-quality work is needed that is relevant to the parts of the world where rheumatic fever is currently most common. More research looking at early (latent) rheumatic heart disease, where the biggest differences may be made, is also needed.

How up-to-date is this evidence?

The evidence is current to 10 March 2024. Whilst this is the most up-to-date review available currently, most of the evidence in this review is from the 1950s to 1960s, so some of the treatments may be outdated.

Key messages

• All the studies only included people with two copies of the most common cystic fibrosis-causing gene variant (F508del).

• Most studies were entirely or partly funded by medicine companies. No studies reported any deaths. None of the single medicines we looked at were clearly better than placebo (dummy treatment) for improving quality of life or lung function, and there was no evidence of the medicines causing more harm than placebo. However, we are unsure about these results.

• The evidence for using a single CFTR modulator is weak, and future research is likely to focus on combination therapies.

What is cystic fibrosis and how can it be treated?

Cystic fibrosis is a serious inherited illness that shortens life. It damages many organs in the body, particularly the lungs, pancreas, and liver. In the lungs, it causes a build-up of thick, sticky mucus that leads to repeated infections and progressive damage. Most people with cystic fibrosis experience breathing difficulties, poor nutrition, and a reduced quality of life.

Cystic fibrosis is caused by a fault in a gene that makes a protein called CFTR. CFTR regulates the movement of salt and water across cell surfaces, keeping the mucus thin and slippery. The most common CFTR gene variant (found in over 80% of people with cystic fibrosis) is F508del, which is a class II variant. People with two copies of F508del usually have more severe disease than people with one copy. In people with class II variants, the CFTR protein is degraded and cannot move properly through the cell. Laboratory experiments suggest that if the protein reaches the cell wall, it may be able to function, restore salt movement, and correct the chronic problems people with cystic fibrosis experience. CFTR modulators are medicines that help the faulty CFTR protein reach the cell wall.

What did we want to find out?

We wanted to know if CFTR modulator monotherapy (single-medicine treatment) can help people of any age with cystic fibrosis who have a class II variant. Specifically, we wanted to know if these medicines can improve survival, quality of life, lung function, and time to the first worsening of lung symptoms. We also wanted to know if this treatment is associated with any unwanted effects.

What did we do?

We searched for studies that investigated the effects of any single CFTR modulator compared with placebo (dummy treatment) or any other single CFTR modulator in people with cystic fibrosis who had at least one copy of a class II variant. We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found 10 studies (with 424 participants, all of whom had two copies of F508del) assessing eight different medicines given as monotherapy. Nine studies included only adults, and one study included people from age 14 years. All the studies were small (including between 18 and 89 participants) and lasted between one day and 29 days. They took place in North America (mainly the USA), Europe, and Australia. Our main findings are for two of the eight medicines, lumacaftor and cavosonstat, which have gone on to be evaluated in larger populations.

Main findings

No studies reported any deaths or meaningful improvements in quality of life. We did not find enough evidence to show any effect of CFTR modulators on lung function. The studies reported a wide range of unwanted effects, but each occurred in only a few participants per study. We did not find enough evidence to support using CFTR modulator monotherapy in people with cystic fibrosis who have two copies of F508del.

What are the limitations of the evidence?

We are not confident in the evidence, for the following reasons.

• The studies were small.

• Most results are based on evidence from a single study.

• The evidence is not applicable to children.

• Not all studies provided enough data for us to analyse the results.

• The evidence related to unwanted effects of treatment was based on very few events.

How up-to-date is this evidence?

This review updates our earlier review of single- and multiple-medicine therapy. The evidence is current to 27 June 2025.

Key messages

• Introducing preterm infants to the smell of maternal breast milk may slightly reduce the time it takes for them to feed fully by mouth. Introducing them to food smells such as vanilla and cinnamon may slightly reduce how often they stop breathing. Finally, introducing preterm babies to the smell of rose or a parent's scent may reduce slightly the time they have to stay in hospital. All other results are very uncertain.

• Future studies should include more infants, use more rigorous designs, and measure outcomes such as breathing problems, low blood oxygen levels, exclusive breastfeeding, and long-term neurodevelopmental outcomes.

What is preterm birth?

A normal pregnancy usually lasts from 37 weeks to 42 weeks. Preterm birth is when a baby is born before 37 weeks of pregnancy. Babies born preterm have not had enough time to fully develop before birth. Their organs may not yet be ready to work on their own, which means they often need intensive medical care and are at greater risk of breathing and feeding difficulties, infection, and problems that can affect their long-term development.

What is olfactory stimulation, and how does it work?

Preterm infants often take time to build up the skills or physical capacity to feed by mouth, and in the meantime are fed through a tube passed into the stomach. Olfactory stimulation involves introducing smells to preterm infants while they are in hospital to see if it helps them start breastfeeding more quickly. These smells include breast milk, food smells such as vanilla or cinnamon, and other smells such as a floral scent or a parent's scent.

What did we want to find out?

We wanted to find out whether introducing a smell to preterm infants in hospital could be helpful and safe for their short-term and long-term well-being. More specifically, we wanted to find out whether introducing a smell to preterm infants is better than placebo (dummy treatment), no treatment, or usual care for:

• reducing the number of infants who have apnea (brief pauses in breathing);

• reducing the number of infants with low oxygen levels in the blood;

• reducing the time spent in hospital;

• reducing the time needed for the infants to learn to feed fully by mouth;

• increasing the number of infants that are fed only with breast milk;

• reducing the number of infants with blindness or deafness between 18 and 24 months of age.

What did we do?

We searched for studies that compared olfactory stimulation with placebo, no treatment, or usual care in preterm infants.

We summarized the results of the studies and rated our confidence in the evidence based on factors such as study size (number of infants) and methods.

What did we find?

We included 14 studies with 1087 infants. Nine studies used the smell of maternal breast milk, five used food-associated smells (vanilla, cinnamon, or anise), and three studies used other smells (rose or parents' scent). All studies compared these smells with no treatment, placebo, or usual care.

Main results

Introducing the smell of maternal breast milk may reduce slightly the time it takes infants to feed fully by mouth. It is unclear whether stimulation with this smell has any effect on how often infants have apnea episodes and how long they stay in hospital.

Introducing the smell of cinnamon, vanilla, or anise may slightly reduce how often infants have apnea episodes. It is unclear whether stimulation with these smells has any effect on how long infants stay in hospital or how long it takes them to feed fully by mouth.

Introducing the scent of rose or a parent's scent may slightly reduce how long infants spend in hospital. It is unclear whether stimulation with these smells has any effect on how often infants have apnea episodes or how long it takes them to feed fully by mouth.

What are the limitations of the evidence?

We have little confidence in these results, as the studies included could have been better designed and included more babies. Several studies did not report outcomes we were interested in.

How up to date is this evidence?

The evidence is current to 2 April 2025.

Key messages

• Tailored education (staff, patient/family and multicomponent) probably reduces the rate of falls and risk of falling.

• Service model changes (where there is a change in the way a hospital delivers care to patients with the goal of reducing falls) in acute hospitals probably reduce the rate of falls.

• Multifactorial interventions (where two or more categories of intervention are given based on an assessment of a person's risk factors for falling) probably reduce the rate of falls and risk of falling, although it is also possible these interventions have no effect or slightly increase falls.

• Exercise may have little or no effect on the risk of falling in hospital settings overall.

• Across all intervention types, fall prevention approaches that include integration with the local setting, tailoring approaches to the needs and abilities of patients, and engaging patients and/or family or carers may reduce the rate of falls in older people in hospitals.

• Further research on the effectiveness of all intervention types aiming to prevent falls in hospitals is needed, particularly for people with cognitive impairment (memory or thinking problems) and in low- and middle-income countries.

Why is reducing falls in older people in hospitals important?

Falls by older people in hospitals are common events that may cause loss of independence, injuries, and sometimes death. Effective interventions to prevent falls are therefore important.

How do we report the interventions used to assess falls?

Trials testing interventions designed to reduce falls in older people are grouped by type, guided by the fall prevention classification system (taxonomy) developed by the Prevention of Falls Network Europe (ProFaNE).

Interventions are classified as single, multifactorial, or multiple, as follows.

• Single interventions: one category of intervention is delivered to all participants in the group. Categories include exercise, interventions aiming to improve medication prescribing (medication optimisation), environment/assistive technology, education, and service model change (where there is a change in the way a hospital delivers care to patients with the goal of reducing falls). Interventions designed to provide education about falls and falls prevention to staff and/or patients or family members are grouped together.

• Multifactorial interventions: two or more categories of intervention are given based on an assessment of a person's risk factors for falling. 

• Multiple interventions: the same combination of interventions is delivered to all participants.

What did we want to find out?

We wanted to know which interventions reduce falls in older people in hospitals in terms of the rate of falls (the actual number of falls over a period of time) and risk of falling (the likelihood that an individual will experience a fall). We also examined the impact on risk of fractures, unwanted effects, and economic outcomes.

What did we do?

We searched for studies that compared falls outcomes in people who received fall prevention interventions with falls outcomes in people who did not receive fall prevention interventions. We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found 55 studies involving a total of 104,474 participants. On average, participants were 79 years old, and 45% were women.

• Education (staff, patient/family and multicomponent) probably reduces the rate of falls and risk of falling.

• Service model changes in acute hospitals probably reduce the rate of falls. We are uncertain about the effect of service model changes on the risk of falling. There were no trials of service model changes in subacute settings.

• We are uncertain about the effect of exercise on the rate of falls. Exercise may have little or no effect on the risk of falling in hospital settings overall.

• We are uncertain about the effect of medication optimisation on falls.

• Multifactorial interventions probably reduce the rate of falls and risk of falling, although it is also possible these interventions have no effect or slightly increase falls.

What are the limitations of the evidence?

We have moderate to very low confidence in the evidence. Our confidence was limited because people in most of the trials were aware of which treatment they were getting, and not all studies provided information about everything that we were interested in. Also, there were problems with the way data were collected in some studies.

How up-to-date is the evidence?

This review updates previous versions of the review published in 2010, 2012, and 2018. The evidence is current to 28 October 2025.

Key messages

• The imaging tests sono-hysterosalpingography (sono-HSG), hysterosalpingography (HSG), and transvaginal hydrolaparoscopy (THL) can reliably show whether the fallopian tubes are blocked.

• HSG seems to suggest blockage of the tubes when there is none more often than sono-HSG and THL.

• We need more research comparing one test against another, and on fluid-filled tubes and magnetic resonance hysterosalpingography (MR-HSG).

Why is it important to diagnose blocked fallopian tubes?

The fallopian tubes connect the ovaries to the womb (uterus). Blocked tubes can prevent pregnancy, as the egg and sperm cannot meet. Diagnosing blocked tubes (tubal occlusion) and fluid-filled tubes (hydrosalpinx) is essential for choosing the right treatment. Traditionally, keyhole surgery (laparoscopy with dye) is used, but this method is invasive and expensive. Alternative tests have been developed using imaging methods, which are less expensive and less invasive, and can be performed during an outpatient clinic visit.

What are the imaging tests?

• Sono-hysterosalpingography (sono-HSG): salt water or foam is placed in the womb, and an internal ultrasound is used to see if the fluid passes through the fallopian tubes.

• Hysterosalpingography (HSG): a contrast fluid is placed in the womb, and X-ray pictures show whether it flows through the tubes.

• Transvaginal hydrolaparoscopy (THL): a tiny camera is placed through the vaginal wall. At the same time, salt water is placed in the womb to see if it comes through the tubes.

• Magnetic resonance hysterosalpingography (MR-HSG): similar to HSG, but a magnetic resonance imaging (MRI) scan is used to make detailed pictures of the tubes.

What did we want to find out?

We wanted to find out how well these tests can show blocked fallopian tubes and fluid-filled tubes, compared with the traditional keyhole surgery test.

What did we do?

We looked for studies that investigated these imaging tests compared to traditional keyhole surgery. We brought together the results from all the studies and checked how well each test could correctly show when the tubes are blocked and when they are fluid-filled.

What did we find?

The review included 21 studies with a total of 1939 women:

• 8 studies on sono-HSG;

• 8 studies on HSG;

• 3 studies for TLH;

• no studies for MR-HSG;

• 2 studies for sono-HSG and HSG

Only two studies on sono-HSG and two studies on HSG reported on fluid-filled tubes.

Three studies were not in English; we translated them online. Nine studies did not clearly explain whether the participants were women with a low or high risk of having blocked tubes. Seven studies did not mention whether the tests were done by a trained person.

Blocked tubes

Sono-HSG, HSG and THL are reliable tests for blocked fallopian tubes. HSG may be more likely than sono-HSG and THL to suggest that tubes are blocked when they are not.

If 1000 women were tested for blocked fallopian tubes by the different imaging tests, and 182 of them actually had blockages in both tubes (this number was based on how often the condition was actually found in the studies we included), then:

• for sono-HSG: 186 women would be told they have blocked tubes based on sono-HSG results. Of these, 8 women would actually have open tubes; 814 women would be told their tubes are open, and of these, 4 women would actually have blocked tubes.

• for HSG: 189 women would be told they have blocked tubes based on HSG results. Of these, 49 women would actually have open tubes; 811 women would be told their tubes are open, and of these, 57 women would actually have blocked tubes.

• for THL: 181 women would be told they have blocked tubes based on THL results. Of these, 8 women would actually have open tubes; 819 women would be told their tubes are open, and of these, 9 women would actually have blocked tubes.

Fluid-filled tubes

• One sono-HSG study reported results by tube and the other reported results by woman, so we could not combine their results.

• Two HSG studies reported results by tube. They showed that all women diagnosed with fluid-filled tubes had this condition, and four out of 100 women diagnosed with fluid-filled tubes did not have this condition.

What are the limitations of the evidence?

The included studies looked at blockages in a single tube, on one side, or on both sides. Only a few studies reported each of these things for each test, so it was difficult to draw conclusions. Also, only a few studies compared one imaging test against another, so we could not say for sure which test is better.

How up to date is this evidence?

The evidence is up to date to November 2023.

Key messages

• Offering counselling plus nicotine replacement therapy (a treatment that provides nicotine in a safer form than tobacco smoking to help people reduce cravings and withdrawal symptoms), during a stay in a psychiatric ward, and continuing this support after leaving hospital, may help more people to stop (quit) smoking tobacco (when measured six months later) than usual care.

• We did not find enough information to draw conclusions about the effects of any other smoking cessation interventions initiated in the psychiatry inpatient setting. We need more, better designed studies that test different ways to help people quit smoking, particularly medicines.

Why is smoking a problem for people with mental illness?

People experiencing mental illness die up to 15 to 20 years earlier than people in the general population from preventable physical illnesses, such as heart and blood vessel disease, airway and lung disease, diabetes, and cancer. Smoking tobacco is one of the main causes of these illnesses. People being treated in hospital for mental illness smoke more than people in the general population and are less successful at quitting, despite wanting to stop. Many hospitals are smoke-free environments and should be a good place to deliver quit-smoking programmes to people with mental illness.

What did we want to find out?

We wanted to know whether quit-smoking programmes started while people are being treated in a hospital psychiatry ward help these people to stop smoking, and which programmes are most effective. We were particularly interested in how many people were still not smoking after six months and whether anyone suffered any serious unwanted effects, such as death or a life-threatening event.

What did we do?

We searched for studies that investigated any quit-smoking programme started in a psychiatric ward compared to usual care, being put on a waiting list, or receiving a placebo (a ‘fake’ medicine with no active ingredients). People taking part could have any psychiatric diagnosis but had to be adults (aged 18 years and older) who were tobacco smokers.

We summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 10 studies that included a total of 2262 people in emergency or long-stay psychiatry wards. Most studies included people with a variety of mental health diagnoses (for example, mood disorders, anxiety disorders, schizophrenia), and three studies involved only people with schizophrenia or schizophrenia-type disorders. The studies took place in five countries (Australia, USA, Taiwan, Israel, and Iran).

The programmes included:

• counselling plus nicotine replacement therapy and continued support with quitting smoking after leaving hospital (versus usual care);

• a group behavioural (psychological support without medicine) smoking reduction programme (versus being put on a waiting list);

• medicines including bupropion (versus placebo) or cytisine (versus nicotine replacement therapy);

• comparisons between different types and doses of nicotine replacement therapy.

Main results

Counselling plus nicotine replacement therapy together with continued support after leaving hospital compared with usual care (5 studies, 1611 people):

• may increase the number of people who are still not smoking six months after leaving hospital by about 6 more people per 100; and

• may result in fewer deaths (1 less death per 100 people), but this result is very uncertain.

What are the limitations of the evidence?

Our results are based on a limited number of studies, and our confidence in the evidence is low. We had very low confidence in the result for deaths because there were very few deaths in the studies.

Anti-smoking medicines, such as varenicline, have previously been shown to work for people with mental illness in the community, but we found no studies that tested their use in a hospital psychiatry ward.

How up to date is this evidence?

This review is up to date to 10 February 2026.

Key messages

• School-based programmes may prevent adolescents from starting to use electronic cigarettes (e-cigarettes) and a community-based programme delivered by text message probably helps adolescents quit using e-cigarettes.

• The evidence is very limited because only three studies contributed to the results.

• Another 30 studies are underway, and we have five more published studies to check. They may provide more answers in the future.

What are electronic cigarettes?

E-cigarettes, also known as vapes, are battery-operated devices that heat a liquid and produce an aerosol (a mix of small particles released in the air) which is inhaled through the mouth into the lungs. They can include electronic cigars, 'snus' (a Swedish tobacco device) or water pipes, and may or may not contain nicotine.

It was generally thought that these devices might lead to people stopping smoking ('current-users') and it is clear that they help adults to quit. However, young people who are not smoking ('never-users') are more likely to try these devices, and they can cause harm to the lungs, such as asthma and effects on development and learning.

What type of programmes are used to stop children and adolescents from using e-cigarettes?

The types of programmes included: education, training and communication (either community- or school-based) or public announcements; other programmes could include family strategies, medicines or counselling, all designed to influence children or adolescents to prevent or stop e-cigarette use.

What did we want to find out?

We wanted to find out:

• whether programmes designed to prevent children and adolescents from starting to use e-cigarettes, or to quit using them, are effective;

• if the programmes had any unwanted effects on children's and adolescents' health, or on the organisations that delivered them.

What did we do?

We searched for studies that investigated programmes to prevent children and adolescents from starting to use e-cigarettes (never-users) or to help them quit using e-cigarettes (current-users).

• Studies could compare programmes with no programme, being on a waiting-list for a programme or another general health programme. The programmes had to be delivered in the community, school, health services, hospitals, or the home.

• People had to be children or adolescents aged 19 years or younger, but also included their parents or caregivers and health professionals.

• The use of tobacco was measured either in the laboratory or by parent- or self-reports, questionnaires or surveys.

We compared and summarised the results, and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found three studies with 10,510 adolescents.

• All participants in the studies were adolescents, with an age range from 12 to 17 years.

• Two of the studies (undertaken in Sweden and Australia) were delivered in schools. The Swedish study (1176 adolescents) lasted three years and required an agreement signed between caregivers or parents and the adolescent pledging to not take up smoking; they also received an annual education session. This programme was compared with four annual educational sessions. The Australian study (7654 adolescents) had four weeks of programmes (40-minute lessons) and was compared with the usual health curriculum.

• One US prevention study (with 1681 current-users), delivered in the community, used a text-based message system which lasted four or 14 weeks (depending on whether a quit date was given or no quit date was given, respectively). It was compared with either monthly text messages that reported e-cigarette use or a waiting-list control (that is, people on a waiting list to receive treatment).

Main results

• The two combined studies found that school-based programmes may help prevent adolescents from ever trying e-cigarettes, but we are very uncertain about the results: 31% of adolescents on school programmes may be prevented from using e-cigarettes compared to 33% of those on an alternative programme (two studies, 8830 people).

• The remaining study found that a community-based programme (for current-users) probably helps adolescents quit e-cigarette use: 45% of adolescents on the programme reported continuing the use of e-cigarettes compared to 62% with an alternative programme or a waiting-list (1 study, 1681 people).

• No studies provided information on the unwanted effects of the programmes.

What are the limitations of this evidence?

Given that the review only included three studies, very limited evidence is available for us to determine what programmes may work to help prevent or stop adolescent e-cigarette use. Our confidence in the evidence was very low-to-moderate because there were very few studies found, the programmes were different, and the studies lasted for different time periods.

How up-to-date is this evidence?

This evidence is current to September 1, 2025. This updates our previous review published in 2024.