Key messages

• Caffeine is an effective medication used to decrease the risk of death or avoid serious lung damage in premature babies, but more research is necessary to fully understand when this therapy should be started.

• The evidence is uncertain when caffeine therapy should be started in preterm babies.

• Upcoming studies should examine different timeframes and different reasons for giving caffeine to preterm infants because, based on current studies, we cannot draw a solid conclusion.

What is caffeine?

Caffeine is the most popular medication used in preterm infants for apnea (pauses in breathing) and to decrease risk of death and other consequences of preterm birth.

Why is caffeine important for preterm babies in the neonatal intensive care unit (NICU)?

Preterm infants requiring special and intensive care usually have problems with breathing, leading to organ damage, including brain damage. Caffeine helps preterm infants to breathe and decreases the risk of death or avoids serious lung damage in premature babies.

What did we find out?

We wanted to know what the best time and reason to start therapy with caffeine is in preterm infants, and how does it affects:

• baby death for any reason;

• long-term lung disease;

• any negative effects of caffeine use that lead to stopping the therapy;

• how long a baby may have to be ventilated;

• how long a baby may need to stay in hospital;

• the number of infants with at least one episode of apnea;

• intermittent hypoxemia (short drops in oxygen levels).

What did we do?

We checked 11 studies that used caffeine within different timeframes and for different reasons, that is to say, caffeine given:

• within two hours of life versus 2 to 24 hours;

• within 72 hours of life versus after 72 hours of life;

• within 72 hours of life versus treatment of infants with sympthoms;

• with minimal symptoms versus caffeine started with serious apnea (who needed help to start breathing again with touch or breathing support);

• during treatment with respirator versus caffeine started at the time of extubation (removal of the breathing tube).

We analyzed and summarized the results of studies and graded our confidence in the evidence, based on how studies were conducted and their size.

What we did find?

We included 11 studies with 774 babies, published between 2014 and 2023. We found seven ongoing studies.

What are the main results?

• The evidence is very uncertain for outcomes reported in comparisons: caffeine within two hours of life versus 2 to 24 hours, and caffeine within 72 hours of life versus after 72 hours of life. However, caffeine within 72 hours of life is likely to reduce the risk for apnea and long-term lung disease.

• Caffeine given within 72 hours of life is likely to reduce the risk of long-term lung disease compared to treating infants who have symptoms. We have little confidence or are not confident in the other outcomes in this comparison, because there are not enough studies to be certain about the results of our outcomes.

• No studies compared caffeine started in infants with minimal symptoms in comparison to caffeine started with serious apnea (handled with stimulation or ventilation).

• Caffeine started while on mechanical ventilation may result in a large reduction in how long babies have to be ventilated and may reduce the risk for long-term lung disease compared to caffeine started at the time of removal of the breathing tube.

What are the limitations of the evidence?

We did not find any studies comparing caffeine started in infants with minimal symptoms to caffeine started with serious apnea (handled with stimulation or ventilation). No studies reported intermittent hypoxemia (short drops in oxygen levels). The results of upcoming studies could change the outcomes of this review.

How up to date is this evidence?

The evidence is current to 23 April 2025.

Key messages

• Compared with an inactive (dummy) treatment, aciclovir and penciclovir creams probably speed up cold sore healing by about one day without increasing the risk of unwanted events. Compared with each other, both creams may have a similar effect on healing time and a similar risk of unwanted events. Compared with an inactive treatment, aciclovir tablets may result in little to no difference in cold sore healing time, but valaciclovir tablets speed up healing by about one day.

• Unwanted events were uncommon across treatments.

• Agreeing on a standard set of outcomes for cold sore studies would make research easier to compare and help clinicians worldwide choose better treatments.

What are cold sores?

Cold sores (also known as fever blisters or herpes labialis) are painful blisters that develop around the lips and mouth, caused by the herpes simplex virus. They are common and contagious, and many people who get cold sores get them repeatedly. The discomfort and self-consciousness cold sores cause can affect people's well-being. In some cases, untreated cold sores can lead to severe complications.

What treatments are available for cold sores?

Standard treatments for cold sores aim to stop the virus from multiplying. They include antiviral creams that are applied directly to the sore (such as aciclovir and penciclovir) and antiviral tablets taken by mouth (such as aciclovir and valaciclovir). Other treatments are less widely available or are still experimental.

What did we want to find out?

We wanted to know which treatments for cold sores can speed up healing and relieve symptoms. We also wanted to know whether cold sore treatments have any unwanted effects.

What did we do?

We looked for studies that compared cold sore treatments with dummy treatment (placebo), no treatment, or other active treatments in people with healthy immune systems who get cold sores. We combined data from studies to identify patterns and overall results, and we rated our confidence in the evidence based on factors such as study methods and sizes.

We were mainly interested in the most common cold sore treatments, but we collected evidence for all types of treatment.

What did we find?

We included 87 studies involving 22,631 people (mostly women). The studies took place in Europe, North America, Australia, and Asia, and tested 58 treatments in total. Study lengths varied, but most followed people through a single cold sore episode.

Most studies (84 out of 87) reported how long the cold sore took to heal. Just over half (49 studies) reported information about serious unwanted effects that caused people to stop treatment, and 58 studies reported information about mild or moderate adverse events.

The pharmacological industry funded 43 of the studies, non-profit organisations funded 25, one study reported no funding, and 18 studies did not report their funding source.

Main results

As well as healing time and unwanted events, we were also interested in how treatments affect improvement in symptoms, cold sore severity, and pain severity. However, no studies of the most common treatments provided results that we could analyse for these outcomes.

Antiviral creams compared with placebo

Compared with placebo:

• aciclovir cream probably speeds up cold sore healing time by about one day (evidence from 7 studies with 3475 people) without increasing the risk of serious unwanted events (9 studies, 6574 people) or mild or moderate unwanted events (8 studies, 6525 people);

• penciclovir cream probably speeds up cold sore healing time by about one day (1 study, 528 people), without increasing the risk of serious unwanted events or mild or moderate unwanted events (2 studies, 3598 people).

Antiviral tablets compared with placebo

Compared with placebo:

• aciclovir tablets may have little or no effect on healing time (1 study, 145 people);

• valaciclovir tablets speed up healing by about one day (2 studies, 1218 people).

The aciclovir study did not report information on unwanted events. In the valaciclovir studies, no serious unwanted events occurred, and the number of people with mild or moderate unwanted events was similar in people using valaciclovir and people using placebo (2 studies, 1856 people).

Penciclovir cream compared with aciclovir cream

Penciclovir cream and aciclovir cream may have similar effects on healing time and a similar risk of mild or moderate unwanted events (1 study, 225 people). No serious unwanted events occurred in this study.

Aciclovir cream compared with aciclovir tablets

We were interested in comparing the effect of aciclovir cream and aciclovir tablets, but we found no studies comparing them.

What are the limitations of the evidence?

We have moderate or little confidence in most of the evidence for common cold sore treatments, mainly because the studies were small. Newer treatments such as photodynamic therapy, laser treatments, zinc patches, and topical propolis may provide additional benefits but are supported by limited evidence.

Most studies included adults, so we are less confident about how these treatments work in children. In addition, few studies took place in East Asia and in low-resource settings.

How up to date is this evidence?
This review includes studies published up to 23 September 2025.

Key messages

• There are only small differences between zuclopenthixol acetate and standard treatments: probably more people are sedated (in a sleepy state) at 24 and 48 hours when given zuclopenthixol acetate, and they may need fewer additional doses of benzodiazepines (a type of sedative medicine). Doses of zuclopenthixol acetate of 25 mg to 50 mg per injection may be as effective as doses of 50 mg to 100 mg per injection.

• There may be no clear difference in side effects between zuclopenthixol acetate and standard medications.

• Further high-quality studies are needed to better understand the benefits and risks of zuclopenthixol acetate.

What is schizophrenia?

Schizophrenia is a serious mental health condition that can cause long-term disability and major disruption to daily life. People with schizophrenia may experience difficulty telling the difference between what is real and what is not (psychosis), including hearing voices (auditory hallucinations) or seeing things that are not there (visual hallucinations) and holding strong beliefs that are not true (delusions). These experiences can be frightening and distressing. At times, this distress may lead to aggressive or violent behaviour towards themselves or others. However, people with schizophrenia are also at increased risk of being victims of violence. Managing aggression and violence in people with schizophrenia is important and should aim to reduce negative attitudes from other people (stigma) and promote safe, respectful care.

What medications are used to treat schizophrenia?

Medications have a calming effect (tranquillising effect), reduce the feeling of being very worried or bothered (severe agitation) or aggression, and help induce sleep (sedative effect). Ideally, these medicines should treat psychotic symptoms (such as hallucinations and delusions), not be used too often and cause few side effects (for example, pain at the injection site or involuntary shaking).

Zuclopenthixol acetate is an injectable antipsychotic medication that can last for two to three days. This review examined whether zuclopenthixol acetate is effective for managing psychosis, aggression or violence, compared with other standard medications used in mental health settings.

What did we want to find out?

We wanted to find out if zuclopenthixol acetate was better than the usual medicines to help manage short-term (acute) behaviour changes that people with schizophrenia may have. We looked at how quickly the medicines helped people to feel calm and sleepy, what their overall effect was on the person and their behaviour, and whether there were any unwanted side effects.

What did we do?

We searched for studies that looked at the drug zuclopenthixol acetate given to people with schizophrenia and similar major mental illnesses who were experiencing short-term (acute) behavioural disturbance, compared to other standard treatments. 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 included 11 studies with a total of 714 people. We found only small differences between zuclopenthixol acetate and standard treatments. Probably more people receiving zuclopenthixol acetate were sedated around 24 hours after treatment, but not in the first 15 minutes. People given zuclopenthixol acetate may need fewer doses of benzodiazepines. Doses of zuclopenthixol acetate of 25 mg to 50 mg per injection may be as effective as doses of 50 mg to 100 mg per injection. There may be no clear difference in side effects between zuclopenthixol acetate and standard medications.

What are the limitations of the evidence?

Many of the included studies were small and had weaknesses in their design and reporting, so our confidence in the evidence is limited. Further high-quality studies are needed to better understand the benefits and risks of zuclopenthixol acetate.

How up to date is this evidence?

The evidence in this review is current to September 2025.

Key messages

• In children and adolescents, for whom abnormally shaped red blood cells caused by sickle-cell disease (SCD) put them at high risk of stroke, long-term transfusions of normal red blood cells (RBCs) probably decrease the risk of stroke compared to standard care, and may also decrease the risk of painful crisis (when sickle-shaped RBCs block small blood vessels) and acute chest syndrome (a potentially fatal blockage of vessels in the lungs).

• RBC transfusions may increase the risk of developing an antibody against transfused RBCs and of developing iron overload (too much iron in the blood).

• Most evidence available applies to children with a specific type of SCD (HbSS disease); more evidence is needed for adults and children with other types of SCD.

What is sickle cell disease?

Sickle cell disease (SCD) is a serious, inherited blood disorder where the red blood cells (RBCs), which carry oxygen around the body, become abnormally shaped ('sickled'). Normal RBCs are flexible and disc-shaped, but sickled red blood cells are rigid and crescent shaped. Sickled RBCs are stickier and less flexible than normal RBCs, which can lead to blockage of blood vessels, tissue damage, organ damage, and episodes of severe pain. Sickled RBCs are fragile and break apart easily; this leads to a condition called anaemia (too few RBCs in the blood).

How is sickle cell disease treated?

Transfusions of healthy RBCs are used to treat SCD in different ways:

• a 'top-up' of normal, non-sickle-cell blood can be given for anaemia;

• an 'exchange transfusion' where some of a person's sickle-cell blood is removed and replaced with normal blood. This reduces the proportion of sickled RBCs and can relieve emergencies, such as stroke or acute chest syndrome;

• long-term, regular – usually monthly – transfusions for prevention of stroke, especially when medications, such as hydroxycarbamide (to decrease the likelihood of painful crises), don't work.

What did we want to find out?

We wanted to find out when RBC transfusions should be used in SCD to prevent:

• death due to any cause;

• SCD complications, such as stroke, acute chest syndrome, painful crises.

We also wanted to know about any unwanted effects from RBC transfusions, such as:

• transfusion reactions (allergic reactions, breakdown of RBCs, fever);

• development of antibodies against the transfused RBCs (when a person's body fights against the transfused blood);

• build up of too much iron in organs such as the liver, heart and pancreas (iron overload).

We looked at several ways that RBC transfusions could be used:

• RBC transfusions versus no RBC transfusions;

• RBC transfusions plus normal care (painkillers, fluids via a drip, oxygen) versus normal care only;

• RBC transfusions versus medicines (e.g. hydroxycarbamide) to reduce the complications of SCD;

• RBC transfusions to reverse anaemia versus exchange transfusions to lower the proportion of sickle cells in blood.

What did we do?

We searched for Cochrane reviews that analysed evidence from studies that had investigated how well RBC transfusions prevented or treated SCD complications. This overview summarises the results of these reviews, and is an update of a previously published Cochrane overview.

What did we find?

We found 17 relevant reviews, however, only 5 reviews had found studies that provided evidence about the effects of RBC transfusion and had results that we could use (9 studies, 1502 participants).

All 9 studies were conducted in high-income countries (USA, Canada, France, UK), so their findings may not be very helpful for low- and middle-income countries, where transfusions are not readily available and transfusion-associated risks differ.

Most of the evidence related to children with the HbSS version of SCD. There was very little evidence about adults with SCD-related complications, and important information, such as quality of life, were often not measured or reported.

The 5 reviews showed there may be little or no difference in the risk of death with any of the treatments (death was very rare). We found that in children and adolescents with a high risk of stroke (identified by a specialised ultrasound test), or who have had a 'silent stroke' (a stroke with no outward symptoms), long-term RBC transfusions compared to standard care:

• probably decrease the risk of stroke;

• may decrease the risk of painful crisis and acute chest syndrome; and

• may decrease the risk of silent stroke in children with abnormal ultrasound results.

However, RBC transfusions may be associated with an increased risk of developing antibodies against transfused RBCs and of developing iron overload.

What are the limitations of the evidence?

There is very little evidence about RBC transfusion for complications of SCD. Most of the evidence applies only to children with a specific type of SCD (HbSS disease). People with SCD are living longer, so we need better evidence about when and how to use RBC transfusions to treat adults with SCD, and how to treat children with other types of SCD.

How up to date is the evidence?

The evidence is up to date to June 2026.

Key messages

• Newborn babies sometimes get infections caused by fungi entering the baby's bloodstream or deep body tissues (invasive fungal infections). It is unclear if one type of medicine that kills the fungi or stops it growing (antifungal treatment) is better than another antifungal treatment in reducing the risk of death, having to stop treatment due to unwanted side effects, or how long the baby stays in hospital. However, this conclusion is based on a few small studies.

• Large, well-designed studies are needed to evaluate the benefits and potential harms of antifungal medicines to treat invasive fungal infection in newborn babies.

What is an invasive fungal infection?

An invasive fungal infection is when fungi enter the baby's bloodstream or deep body tissues. Invasive fungal infections are usually caused by Candida, which is a yeast infection. Invasive fungal infections are serious and are the major cause of death and serious illness in babies born early (preterm).

How are invasive fungal infections treated?

Invasive fungal infections are commonly treated with a variety of medicines that kill fungi or stop fungi growing (antifungal medicines), such as:

• polyenes (e.g. amphotericin B);

• azoles (e.g. fluconazole);

• echinocandins (e.g. micafungin, caspofungin); and

• antimetabolites (5-fluorocytosine).

What did we want to find out?

We wanted to find out if any particular antifungal medicine or combination of antifungal medicines was better to improve:

• the risk of the baby dying (for any reason) before leaving the hospital;

• development of the baby's nervous system (neurodevelopment) by the time the baby is two years old;

• the risk of having to give a higher dose of the antifungal medicine, or adding another antifungal medicine, because the infection is not getting better or is worsening;

• how long babies stay in hospital; and

• unwanted or harmful effects of antifungal medicines (meaning the medicine has to be stopped).

What did we do?

We searched for studies that investigated antifungal medicines (or combinations of antifungal medicines) in newborn babies, either born early (preterm) or at the usual time (full-term). 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 that involved 229 newborn babies with invasive fungal infections. One study only included preterm babies and the others included both preterm and full-term babies. One study compared fluconazole with amphotericin B; two studies compared micafungin with amphotericin B; two studies compared caspofungin with amphotericin B; and one study compared micafungin with fluconazole.

Main results

It is unclear if one antifungal treatment is better than another antifungal treatment at reducing the risk of a baby dying in hospital or having to stop the medicine due to its unwanted or harmful side effects.

It is unclear if fluconazole or micafungin, compared to amphotericin B, may reduce the number of days that newborn babies with invasive fungal infections have to stay in hospital.

What are the limitations of the evidence?

We are not confident in the evidence. This is because some studies had limitations in the way they were conducted. For example, the researchers were aware of the treatment received by the babies, which could have influenced the results. In addition, the evidence does not cover all the outcomes we were interested in. There were not enough studies to be certain about the results and the studies were very small.

How up to date is this evidence?

This review updates our previous review first published in 2004 and updated in 2012. The evidence is up to date to November 2025.

Key messages

In people undergoing surgery for rectal cancer:

• Using a soft tube (transanal tube) placed through the anus (end of the bowel where stools come out) may reduce the need for further surgery due to bowel leakage. However, it is uncertain whether the tube reduces the chance of leakage itself.

• This finding changed according to whether people had a temporary opening in the bowel (a diverting stoma). Among people with a diverting stoma, leakage was more frequent with a transanal tube than without one.

• More research is needed to identify which people are most likely to benefit from a transanal tube and to better understand the possible benefits and risks.

What is anastomotic leakage?

After rectal cancer surgery, the surgeon needs to reconnect the bowel. This connection is called anastomosis. Sometimes the anastomosis does not heal properly, allowing bowel contents to leak into the abdomen. This is called anastomotic leakage. It can cause a serious infection and make recovery more difficult.

How can leakage be prevented?

One common way to help prevent leakage is by creating a temporary opening in the bowel, called a diverting stoma. This allows stool to leave the body without passing through the healing bowel connection. However, a diverting stoma can lead to complications and requires another operation to close it.

Another option is placing a soft tube through the anus so that it lies near the bowel connection. This is called a transanal tube. The tube may reduce pressure, improve drainage, and help reduce the risk of leakage.

What did we want to find out?

We wanted to find out whether using a transanal tube during rectal cancer surgery:

• lowers the risk of anastomotic leakage;

• lowers the need for further surgery;

• causes any unwanted effects or other problems.

What did we do?
We searched for studies that compared using a transanal tube with not using one in adults undergoing rectal cancer surgery. We compared and summarised the results of the studies and assessed how confident we were in the evidence.

What did we find?

We found four studies involving 1318 people undergoing rectal cancer surgery. About half had a transanal tube placed during surgery, and the others did not. Studies took place in Denmark, Japan and China and most lasted up to 30 days after surgery. One study did not use a diverting stoma. Different types of tube were used, and they were put in place for 3 to 7 days. Different types of surgery were also used.

Main results

Compared with not using a tube, it is uncertain whether a transanal tube lowers the chance of leakage (4 studies, 1318 people). For every 1000 people having surgery, the risk of anastomotic leakage would be 83 in those without a tube compared to 73 with a tube. However:

• It may reduce the need for further surgery to treat leakage (3 studies, 1124 people). For every 1000 people having surgery, the risk of further surgery would be 45 in those without a tube compared to 14 in those with a tube;

• It may reduce the length of hospital stay after surgery, although this finding was based on one study with 398 people. Those who had a transanal tube placed were discharged from hospital an average of 3.25 days earlier than those without a tube;

• It may cause other problems, such as pain or discomfort, but the evidence is unclear. About 1 in 4 people reported pain or discomfort, and a few had the tube come out earlier than planned.

• The results for leakage changed according to whether people had a diverting stoma. Among people with a diverting stoma, leakage was more frequent with a transanal tube than without one.

What are the limitations of the evidence?

The studies were generally small, and the results varied between studies. Some studies also had limitations in how they were conducted or reported. Because of this, we are not confident about many of the results, and more research is needed to better understand which people are most likely to benefit from a transanal tube and its possible unwanted effects.

How up to date is this evidence?

The evidence is current to 6 August 2025.

Key messages

• The effects of using a T-tube (a small drain placed in the duct that carries bile) on the risk of death from any cause, bile leaks, the need for a new transplant, and unwanted biliary events are unclear.

• It is unclear whether using a T-tube during bile duct surgery in adults having a liver transplant helps keep the bile duct open or increases complications caused by the drain itself.

• No study reported quality of life.

What is liver transplantation and biliary reconstruction?

Liver transplantation is an operation that replaces a severely diseased liver of a person with a healthy one from a donor. It is the definitive treatment for people with severe, end-stage liver disease or liver cancer. During this surgery, a critical step is joining the new liver's bile duct to the recipient's own bile duct (a technique called anastomosis). The bile duct is the tube that carries bile (a fluid that helps with digestion) from the liver to the intestine. Problems with this connection, such as leaks or narrowing, are important causes of illness and death after a transplant.

What is a T-tube?

A T-tube is a medical device (a small drain) placed in the bile duct during surgery. It is intended to help drain bile and allow doctors to check if the flow is blocked. There is no agreement among surgeons on whether using this tube helps prevent problems or whether the device itself causes new complications, such as infections or blockages.

What did we want to find out?

We wanted to find out if using a T-tube was better or worse than not using a drain in adults undergoing liver transplantation. We focused on:

• risk of death;

• serious bile duct complications (such as bile leaks or narrowing of the duct (stenosis));

• the need for a new transplant;

• quality of life.

What did we do?

We searched for studies that compared using a T-tube with not using one in adults who had a liver transplant. We compared and summarised the results of these studies and rated our confidence in the information, based on factors such as how the studies were performed and their size.

What did we find?

We found six studies involving 844 adults. These studies were conducted in Spain, France, the UK, and Germany, and were published between 1996 and 2013. Most studies lasted for at least 21 months (4 studies). Most participants were men (about 61%) with an average age of 54 years.

We have very little confidence in the results, so we cannot be certain of the effects of the T-tube.

• Death from any cause: we do not know whether using the T-tube makes a difference.

• Narrowing of the duct: using a T-tube may reduce the risk of bile duct narrowing, but the impact on the recipient is unclear.

• Bile leaks: we do not know whether using the T-tube affects the risk of bile leaking from the connection.

• Complications from the drain: using the T-tube itself may increase the risk of problems. However, we are very uncertain about the results.

• Retransplantation: we do not know whether the use of a T-tube affects the need for a new transplant.

• Unwanted biliary adverse events: we do not know whether using the T-tube makes a difference.

• No studies have provided information on quality of life.

What are the limitations of the evidence?

We have very little confidence in the results. The studies did not provide adequate information about how they were conducted, which is likely to introduce errors in their results. The studies were small, and the results varied widely across the studies.

No new studies have been published on this topic since 2013. All the included studies were conducted in European centres. Our results cannot be generalised to populations with different social and economic backgrounds. Since the last study included in this review was published, changes to transplantation practice have occurred. These changes affect donor selection for liver transplantation and organ preservation until they are transplanted into the person who needs it. Therefore, our findings may not apply to current transplantation practice.

How up to date is this evidence?

The evidence is up to date to 28 April 2026.

Key messages

• Combined treatments that are tailored to someone’s risk factors (multifactorial approaches) may slightly reduce the number of falls and the chance of falling two or more times compared with no special falls prevention treatment (usual care). However, compared with exercise or falls education, the benefit becomes very small or disappears.

• Combined treatments where everyone receives the same treatment (multiple component approaches) may provide little or no additional benefit compared to usual care, exercise, or falls advice or education, except that they may reduce the chance of falling compared with usual care.

• More research is needed into why falls happen, when and where they are most likely to happen, and how to measure the effects of treatment.

How can we prevent falls in older people, and why is this important?

Falls are one of the most common causes of injury and death in older people worldwide. People may be at risk of falling for a number of reasons (their 'risk factors' for falling), such as previous falls, muscle weakness, and balance problems, as well as hazards in the environment and inappropriate footwear. Falls prevention treatments used include exercise, education, counselling, and medication review.

Multifactorial falls prevention approaches refer to combined treatments that are tailored to an individual's specific risk factors. In contrast, multiple component falls prevention approaches are standardised combinations of treatments. These treatments may be compared with no special falls prevention treatment (usual care), exercise, or falls prevention education (such as a leaflet).

What did we want to find out?

We wanted to know, in older people living in the community, whether multifactorial or multiple component falls prevention treatments:

• reduce the number of falls;

• reduce the chance of falling at least once and the chance of falling two or more times;

• cause any unwanted effects.

What did we do?

We searched for studies that compared multifactorial or multiple component falls prevention treatments to exercise, usual care, or falls prevention education. 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 110 studies involving 48,919 older people. Of these:

• 65 studies looked at multifactorial treatments;

• 44 studies looked at multiple component treatments; and

• 1 study looked at both types of treatments.

The studies were performed worldwide, mostly in Australia, the UK, and the USA. The average age of participants ranged from 62 to 85 years. Most studies included more women than men, and most lasted around 12 months.

Main resultsMultifactorial falls prevention treatments:

• versus usual care may reduce the number of falls (29 studies, 9442 people) and the risk of falling two or more times (17 studies, 4826 people); and may have little or no effect on the risk of falling at least once (38 studies, 12,774 people).

• versus exercise may or may not make a difference to the number of falls and the risk of falling at least once – the evidence is very uncertain. No studies tested the risk of falling two or more times.

• versus falls advice or education provide no additional benefit and likely increase the number of falls by a small amount (7 studies, 9901 people). They probably have little or no effect on the risk of falling at least once (7 studies, 8850 people) and the risk of falling two or more times (3 studies, 7865 participants).

Multiple component falls prevention treatments:

• versus usual care may have little or no effect on the number of falls (14 studies, 4026 people) and may reduce the risk of falling at least once (19 studies, 6925 people). The evidence for the risk of falling two or more times is very uncertain.

• versus exercise may have little or no effect on the number of falls (8 studies, 2160 people) and the risk of falling two or more times (5 studies, 874 people). They likely have little or no effect on the risk of falling at least once (10 studies, 2920 people).

• versus falls advice or education may have little or no effect on the number of falls (7 studies, 9313 people) and the risk of falling at least once (8 studies, 9355 people). They likely have little or no effect on the risk of falling two or more times (6 studies, 8725 people).

Unwanted effects were generally mild.

What are the limitations of the evidence?

We have only moderate to very low confidence in the evidence because:

• the results varied across studies;

• in most studies, people likely knew which treatment they were receiving;

• not all studies measured everything we were interested in; and

• the benefits we found might be overestimated, because studies with smaller or negative results are less likely to be published.

How up to date is this review?

This review updates an earlier version from 2018. The evidence is current to May 2024.

Key messages

• Compared to levonorgestrel (a common emergency contraception pill), mifepristone probably results in fewer pregnancies. It is also probably more effective at preventing pregnancy than the Yuzpe method (a combination of emergency pills).

• Mifepristone's main unwanted effect is that it delays a woman's next period; this is more likely to happen with higher doses.

• Future studies should investigate whether the time interval between unprotected sex and taking mifepristone (e.g. one day versus five days or more) reduces its effectiveness, and explore how acceptable women find different emergency contraception treatments.

What is emergency contraception?

Emergency contraception is used to prevent pregnancy after unprotected sex, the failure of another birth control method (e.g. broken condom), or in cases of sexual assault. Common methods of emergency contraception include copper intrauterine devices (IUDs) and pills (known as 'morning-after pills').

IUDs are small, T-shaped frames inserted into the uterus. They prevent pregnancy by interfering with sperm movement and egg fertilization. They are very effective at preventing pregnancy, but timely access can be difficult because a healthcare professional needs to insert the device.

Emergency contraception pills work by stopping or delaying the release of an egg from the ovary. They include:

• mifepristone, which blocks the hormone progesterone needed for pregnancy;

• levonorgestrel (brand name 'Plan B One-Step'), which tells the body to pause releasing the egg;

• the Yuzpe method, which involves taking two large doses of regular daily birth control pills, about 12 hours apart.

Some emergency contraception pills are expensive and not widely available.

What did we want to find out?

We wanted to find out how mifepristone compares to other emergency contraception methods at preventing pregnancy. We also compared these methods to see if they differed in terms of:

• unwanted effects (such as nausea and vomiting);

• the timing of women's next menstrual period.

What did we do?

We searched for studies that compared giving mifepristone versus other emergency contraception pills or IUDs to reproductive-aged women using emergency contraception to prevent pregnancy (not to terminate an early pregnancy).

We summarized the results of the studies and rated our confidence in the evidence, based on factors such as the studies' methods and number of women involved.

What did we find?

We included 87 studies with around 36,000 women. Most were conducted in China, between 1992 and 2015. The smallest study included 16 women and the largest, 4000. Nearly half (42 studies) compared two different doses of mifepristone, while 41 studies compared mifepristone to levonorgestrel. Five studies compared mifepristone to the Yuzpe method or IUDs.

Main results

Compared to levonorgestrel, a medium dose of mifepristone (25 mg to 50 mg) probably:

• results in fewer pregnancies: if 35 out of 1000 women given levonorgestrel became pregnant, about 23 out of 1000 women would with mifepristone (27 studies, 6052 women);

• reduces the risk of any unwanted effects (17 studies, 4350 women);

• increases the risk of having a late period (17 studies, 3615 women).

Compared to levonorgestrel, a low dose of mifepristone (under 25 mg):

• results in fewer pregnancies: if 20 out of 1000 women given levonorgestrel became pregnant, about 15 out of 1000 given mifepristone would (14 studies, 8752 women);

• probably substantially reduces the risk of any unwanted effects (3 studies, 609 women);

• slightly increases the risk of having a late period (10 studies, 7618 women).

Compared to the Yuzpe method, mifepristone (any dose):

• probably results in fewer pregnancies: if 25 out of 1000 women given the Yuzpe pill combination became pregnant, about 3 out of 1000 women would with mifepristone (3 studies, 2144 women);

• probably substantially reduces the risk of any unwanted effects (2 studies, 1693 women);

• increases the risk of having a late period (3 studies, 1912 women).

Compared to IUDs, we are unsure about the effects of mifepristone on the number of pregnancies, unwanted effects, and late periods (2 studies).

Compared to a low dose of mifepristone (under 25 mg), a medium dose of mifepristone (25 mg to 50 mg):

• results in slightly fewer pregnancies: if 16 out of 1000 women given low-dose mifepristone became pregnant, about 13 out of 1000 would with mid-dose mifepristone (26 studies, 12,358 women);

• may make little to no difference to the risk of experiencing unwanted effects (12 studies, 2908 women);

• slightly increases the risk of having a late period (22 studies, 11,733 women).

What are the limitations of the evidence?

We are moderately or very confident in most of the results. However, many studies did not clearly report their methods, which reduced our confidence in some findings. Most studies were conducted in China, so the results may not apply to women in other parts of the world. We found no studies that compared mifepristone to ulipristal acetate (brand name 'Ella'), a highly effective emergency contraception pill.

How up to date is this evidence?

The evidence is current to February 2025.

Key messages

• For adults on breathing machines (ventilators) in an intensive care unit (ICU), raising the head of the bed to about a 30° to 45° angle instead of lying flat probably reduces lung infections and may shorten the time patients need a ventilator, without changes in death rates during the ICU or overall hospital stay.

• Raising the head of the bed higher (40º to 45º versus 30º; or 30º to 45° versus less than 30º) probably lowers the risk of lung infection but increases the risk of bedsores. Adding side-to-side turning (rotation) to a raised head position probably gives extra benefits, including fewer lung infections and a shorter time on a ventilator, in the ICU and in hospital.

• More large, well-designed trials are needed to determine the optimal bed angle and to assess the effects on survival and potential harms.

What is ventilator-associated pneumonia?

Ventilator-associated pneumonia is a lung infection that develops in patients who have been using a ventilator (a machine that helps with breathing) for more than 48 hours. It is associated with an increased risk of death, longer stay in the ICU and in hospital overall, and greater healthcare costs.

What is 'head-end elevation' or a semi-recumbent position?

Head-end elevation means raising the upper body rather than lying flat. The head of the bed is usually raised between 30° and 45°, although angles from 15° to 60° may be used. This is often called a 'semi‑recumbent' or 'semi‑upright' position.

There are also different types of semi-recumbent positions with additional components; for example:

• semi-recumbent lateral or lateral rotation position where patients are in a semi-recumbent position and also rotated from side to side, either manually or continuously using a motorised turning bed; and

• semi-recumbent rotation position where the head-of-bed angle is rotated through several different degrees (for example, 20º, then 30º, and then 45º).

What did we want to find out?

For ICU patients on ventilators, is raising the head of the bed (semi-recumbent position) better than a flat bed and other bed positions for reducing:

• lung infections;

• death during the ICU stay or overall hospital stay;

• the length of stay in the ICU or hospital;

• the duration of assisted breathing through a ventilator; and

• bedsores?

What did we do?

We searched for studies that compared semi-recumbent positioning with any other positioning, or different degrees or types of semi-recumbent positioning, in ICU adult patients requiring a ventilator. We compared and summarised the results and assessed how confident we are in the findings, based on factors such as the study design and methods.

What did we find?

We found 48 studies involving 7955 patients in ICUs using ventilators. Thirty-seven trials were conducted in China, two in Iran, and one each in Austria, France, India, Spain, Türkiye, the United Kingdom, and the Netherlands. Two studies were conducted across several high-income countries. Participants were typically around 55 years old, and about one-third were women. Study size ranged from 25 to 855 participants.

• Comparing head-end elevation with flat position (17 studies with 2640 participants), raising the head of the bed reduces the risk of lung infections, and may also reduce the duration of assisted breathing through a ventilator, without changes in death rates during ICU stay or overall hospital stay. However, its impact on the length of ICU and hospital stay and bedsores remains uncertain.

• Comparing different levels of head-end elevation (30º to 45° versus less than 30º; 11 studies with 1153 participants, or 40º to 45º versus 30º; 14 studies with 1374 participants), raising the head of the bed higher probably reduces the risk of lung infections, but increases the risk of bedsores. However, these positions may not make a difference in reducing the risk of death during the ICU stay or overall hospital stay. The effects on time spent in ICUs or hospitals, or how long the patient needs assisted breathing with a ventilator machine, remain uncertain.

• Compared to regular head-end elevation (7 studies with 708 participants), adding side-to-side turning probably further reduces the risk of lung infections, and shortens the duration of assisted breathing through a ventilator, as well as the length of stay in both ICU and hospital.

• The effects of raising the head of the bed to a very high angle (60° versus 45°), or using other body positions, are unclear (for example, different rotational positions, positions where patients are lying face down on their stomach, or positions where the patient's feet are lifted to be higher than their head).

What are the limitations of the evidence?

Our confidence in the results is limited. Many studies did not report whether patients remained in their assigned positions, and some did not clearly define lung infections, making the findings less reliable and harder to apply in practice.

How up to date is this evidence?

This updates our previous version of the review, published in 2016. The evidence is current to 3 October 2025.

Key messages

• The evidence is very uncertain about whether neuromuscular electrical stimulation (NMES) (small electrical impulses delivered through the skin to make muscles contract) improves daily activities and independence or affects the risk of death in adults with kidney failure receiving haemodialysis.

• NMES may result in little to no difference in blood pressure or resting heart rate. No studies reported fatigue, pain, infection, or problems with dialysis access.

• More research is needed because many important outcomes, including fatigue, pain, infection, and dialysis access problems, were not reported. None of the studies included adults undergoing peritoneal dialysis.

What is the problem?

Adults with kidney failure (a condition where the kidneys no longer function well enough to keep a person alive) receiving dialysis (a procedure where a machine is used to remove waste products and excess salts and fluid from the blood when the kidneys stop working properly) often experience muscle weakness and loss of strength because of reduced physical activity and the effects of kidney disease. Exercise can help, but many adults on dialysis find it difficult to take part due to fatigue, illness, or limited time. Neuromuscular electrical stimulation (NMES) delivers small electrical impulses through the skin to make muscles contract. This technique can strengthen muscles without the need for voluntary exercise and may be especially helpful for those who cannot take part in active exercise. NMES has been used successfully in other medical conditions, but its effectiveness in adults with kidney failure receiving dialysis is not yet clear.

What did we want to find out?

This review looked at whether NMES can help adults receiving dialysis. We wanted to find out whether it improves daily activities and independence, cardiovascular health, death, fatigue, pain, infection, and problems with dialysis access.

What did we do?

We searched multiple scientific databases for studies that examined the effects of NMES on the legs of adults receiving dialysis. Studies were included if they compared NMES with those who did not receive NMES.

What did we find?

We found 12 studies involving 348 adults with kidney failure receiving haemodialysis. Results from 299 participants were available for one or more outcomes. Most studies were small, lasted between four and 20 weeks, and were carried out in haemodialysis centres across eight countries. In most studies, NMES was applied to the leg muscles during dialysis treatment.

• Only one small study looked at whether NMES helped adults take part in everyday activities and live independently. The evidence was very uncertain, so we do not know whether NMES makes a difference.

• Four studies found that NMES may make little to no difference to blood pressure, and two studies found that it may make little to no difference to resting heart rate.

• One participant receiving usual care died during a study. The evidence was very uncertain, so we do not know whether NMES affects the risk of death.

• No studies measured whether NMES reduced fatigue, pain, infections, or problems with dialysis access.

• None of the studies included adults undergoing peritoneal dialysis.

What are the limitations of the evidence?

We are not very confident in most of the findings. Most studies included only small numbers of people, so it is difficult to know whether the results would be the same in larger groups. Some studies did not clearly describe how they were carried out, making it harder to judge the reliability of the results. Many studies also did not measure or report outcomes that are important to people receiving dialysis, such as fatigue, pain, infection, or problems with dialysis access. The NMES programmes also varied in how they were delivered, so it is difficult to know which treatment programme works best.

How up-to-date is the evidence?

The evidence is based on searches up to June 2025.

Key messages

• Compared with no structured exercise, exercise-based cardiac rehabilitation for people with coronary heart disease reduces heart attacks, likely reduces hospital admissions and may slightly reduce the risk of death.

• Exercise is associated with improved well-being for up to 12 months and it appears to be cost-effective.

• Recent studies include more women, home-based and digital programmes, and more countries worldwide.

What is coronary heart disease?

Coronary heart disease (CHD) is a condition where the main blood vessels to the heart become narrow or blocked, often due to fatty deposits, reducing blood flow to the heart. It is the leading cause of death worldwide. Thanks to improvements in treatment, more people are now surviving CHD and living with its ongoing effects. Many people with CHD experience symptoms such as chest pain (angina) and breathlessness during physical activity, and fatigue. They may also be at risk of future complications, such as heart attacks.

What is exercise-based cardiac rehabilitation?

Exercise-based cardiac rehabilitation is designed to help people with CHD manage their condition, improve their health and reduce the risk of future problems. It includes structured exercise programmes, sometimes combined with education or psychological support.

What did we want to find out?

We wanted to find out if, compared to no structured exercise, people with CHD who participated in exercise-based cardiac rehabilitation had:

• a lower risk of death;

• fewer heart attacks;

• less need for further heart procedures (including stents (tiny tubes that hold the blood vessels open) or bypass surgery); and

• fewer hospital admissions.

We were also interested in whether exercise-based cardiac rehabilitation improved people's well-being and was cost-effective.

What did we do?

We searched for studies that investigated exercise-based cardiac rehabilitation compared to no structured exercise for adults with CHD. People in the studies had to have had a heart attack (myocardial infarction), surgery to restore blood flow to the heart (for example, a coronary artery bypass) or have angina or blocked arteries (coronary artery disease). Exercise could take place in a hospital, in the community, or in people's homes. Studies had to follow people for at least six months.

What did we find?
We found 107 studies with 26,886 people. Most people in these studies had experienced a heart attack or had received bypass surgery or a procedure to open narrowed or blocked blood vessels in the heart (angioplasty). Most studies included both men and women, but women made up only 17% of study participants overall.

Fifty-two studies investigated exercise only. The remaining studies investigated exercise combined with another treatment, such as education, or psychological or social support. The most common exercise was aerobic: static cycling; walking; or circuit training. The frequency and intensity of the exercise varied across studies. Twenty-seven studies looked at exercise in people's homes, with some programmes being delivered via a mobile phone app or online. Most studies followed people for up to 12 months.

Main results

Exercise-based cardiac rehabilitation for between six and 12 months compared with no structured exercise:

• probably reduces deaths from any cause (30 studies, 10,391 people) and may reduce deaths from heart-related causes (20 studies, 7277 people). For every 125 people who participate in exercise-based cardiac rehabilitation, one death from any cause is likely to be prevented. Similarly, for every 200 people participating, one death from heart-related causes may be prevented;

• results in a large reduction in heart attacks (25 studies, 8584 people). For every 71 people who participate in exercise-based cardiac rehabilitation, one heart attack is prevented;

• makes little to no difference to the need for further heart procedures (including stents or bypass surgery);

• probably reduces hospital admissions overall (21 studies, 3868 people) where for every 17 people who participate in exercise-based rehabilitation, one hospital admission is likely to be prevented. It may also reduce heart-related hospital admissions (6 studies, 1550 people).

The evidence indicated that people experienced increased well-being with exercise, compared with not participating in a structured exercise programme.

Based on evidence from eight studies, exercise-based cardiac rehabilitation was found to be cost-effective.

What are the limitations of this evidence?

We are very confident in the evidence for heart attack and the need for further heart procedures. However, our confidence in the other evidence is limited because some studies did not use the best methods to carry out their research or report their results. For example, we don't know how well people carried out their exercise programmes. Overall, there are still fewer women than men in the studies. However, many of the new studies that we found were carried out in low- and middle-income countries, so, our results may be more relevant than before for these countries.

How up-to-date is this evidence?

This updates the previous version published in 2021. The evidence is current to March 2026.

Key messages

• In the management of endometriosis (a condition where tissue grows outside the womb), studies that compared a progesterone receptor modulator (PRM; a medicine that changes how the hormone progesterone acts in the body) against placebo (a 'dummy' treatment, or sham treatment, that does not contain any medicine but looks or tastes identical to the medicine being tested) found that a PRM called mifepristone may improve painful periods. However, it may cause hot flushes.

• A PRM called gestrinone may be less effective than medicines known as gonadotropin-releasing hormone (GnRH) analogues (which reduce the amount of oestrogen made by the ovaries) for treating painful periods, but may improve pain during sex. Gestrinone may also cause fewer hot flushes. We do not know how gestrinone compares to a treatment called danazol in terms of pain not related to periods, painful periods or pain during sex. We do not know whether gestrinone or danazol causes more unwanted effects.

• Future studies should compare progesterone receptor modulators with medicines currently used to treat endometriosis symptoms and focus on assessing pain using recognised and reliable methods. Larger, well-designed studies are also needed to assess the benefits and unwanted effects of progesterone receptor modulators other than mifepristone and gestrinone.

What is endometriosis?

Endometriosis is a condition where tissue similar to the lining of the womb (uterus) grows outside the womb. Endometriosis is oestrogen-dependent and thus is seen mainly during the reproductive years. It can cause pain in the tummy area (abdomen), generally during periods (menstruation) or associated with sexual intercourse.

Endometriosis is treated through different types of medical or surgical treatment. Progesterone receptor modulators (PRMs) are medicines that change how the hormone progesterone acts in the body. PRMs include mifepristone, gestrinone, ulipristal acetate, vilaprisan and asoprisnil. Because they can slow down or stop the growth of tissue in the lining of the uterus, they have been suggested as a treatment for endometriosis.

What did we want to find out?

We wanted to know whether, in patients with endometriosis, PRMs are better than placebo ('dummy' treatment), no treatment or other medical treatment for improving overall pain, pain during periods and pain during sexual intercourse.

We also wanted to know if these medications were safe by assessing unwanted effects experienced by patients, such as hot flushes and feeling sick (nausea).

What did we do?

We searched for studies that investigated the effectiveness of PRMs for symptoms associated with endometriosis and whether they caused unwanted effects. 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 included nine studies involving 922 women aged 18 to 45 years. Most studies tested the PRMs mifepristone or gestrinone. One study tested asoprisnil, but the study was published only as a short summary without results that we could use. Two of the studies did not measure any of the effects we were interested in.

Main results

Progesterone receptor modulators versus placebo

When compared to a placebo, mifepristone:

• may reduce painful periods after three months of treatment (based on 1 study of 342 women);

• may cause more unwanted effects, such as hot flushes (1 study, 360 women);

• may make little or no difference to nausea (1 study, 360 women); and

• we are uncertain whether mifepristone reduces pain during sex (1 study, 223 women).

Progesterone receptor modulators versus other medical treatment

When compared to danazol, one study of 38 women showed that:

• we do not know whether gestrinone improves pain symptoms after six months of treatment (1 study, 38 women);

• we do not know whether gestrinone causes more or fewer hot flushes or makes no difference (2 studies, 302 women); and

• gestrinone and danazol may cause similar rates of nausea, but the results are very uncertain (2 studies, 302 women).

When compared to a GnRH analogue (leuprorelin), one study of 55 women found that:

• gestrinone may be less efficient in treating painful periods after six months of treatment (1 study, 55 women); but

• gestrinone may reduce pain during sex (1 study, 52 women);

• gestrinone may be similar to leuprorelin in terms of general pain experienced (1 study, 55 women);

• gestrinone may cause fewer hot flushes and similar levels of nausea (1 study, 55 women).

What are the limitations of the evidence?

Our confidence in the evidence is low to very low, mainly because some studies had one or more of these problems:

• they did not have many people taking part;

• they focused on specific settings or populations;

• they used methods likely to introduce errors in their results;

• they did not clearly report how they were conducted;

• they did not clearly report whether the people taking part knew which treatment they had received, which could have affected the study results.

How up to date is this evidence?

This review updates a previous review. The evidence is up to date to April 2026.

Key messages

• In preterm infants, physical activity programmes may provide a small benefit for bone development and body weight gain over the short term.

• Physical activity programmes may have little to no effect on body length gain.

• We do not know if physical activity programmes affect the risk of fractures (broken bones), and we don't have enough information to assess long-term benefits and harm.

What is poor bone development and growth in preterm infants?

Babies born too early (born before 37 weeks of pregnancy) are often cared for in a way that minimises physical activity to reduce stress and stress-related complications. However, lack of physical activity might lead to poor bone development and growth, particularly in very low birth weight infants (meaning babies born weighing less than 1500 g). This may have long-term consequences, as seen in bedridden children and adults.

What are physical activity programmes?

Physical activity programmes are daily exercise where all joints in the arms and legs are gently moved and pressed for a few minutes each day over several weeks.

What is bone mineralisation?

Bone mineralisation is the process in which minerals, mainly calcium and phosphorus, are added to newly formed bone tissue, making the bone hard and strong.

What did we want to find out?

We wanted to find out whether physical activity programmes given during the initial hospital stay help preterm infants to develop stronger bones and grow better. We planned to assess this at the end of the programme and 12 to 24 months after the expected date of delivery. We also wished to examine whether these programmes affect the risk of fractures (broken bones).

What did we do?

We searched for studies that compared physical activity programmes with no organised programmes in preterm infants.

What did we find?

We included 15 small studies, with 434 infants, in our review.

We found that preterm infants who received a daily physical activity programme for several weeks might have slightly better bone mineralisation and gain in body weight when assessed at completion of the programme, but we are uncertain about the results.

We don't know whether physical activity programmes have a long-term effect on bone mineral content, because none of our included studies gave information on this outcome. We found no evidence that the physical activity programmes reduced or increased body length. We found very uncertain evidence regarding their effect on the frequency of fractures.

What are the limitations of the evidence?

Our confidence in the results is low to very low because many of the included studies were small or had limitations in their methods. When several studies were combined for specific outcomes, the results were often imprecise and inconsistent. Because of this, we are uncertain whether physical activity programmes have meaningful effects on bone mineralisation, weight gain, body length gain or the risk of a fracture.

The evidence only covers outcomes measured during the initial hospital stay, and we do not have evidence about longer-term effects.

How up to date is this evidence?

This review updates our previous review from 2014. The evidence is up to date as of October 2025.

Key messages

• Giving vitamin D supplements to babies born early (preterm: before 37 weeks of gestation) and with a low birth weight (less than 2500 g) probably reduces the risk of vitamin D deficiency (vitamin D level under 30 nmol/L) and insufficiency (vitamin D level under 50 nmol/L).

• Higher doses (800 IU/day and more) compared to lower doses (200 IU to less than 800 IU/day) of vitamin D in preterm babies probably reduce the likelihood of vitamin D deficiency. However, higher doses may also result in excessive vitamin D levels in some preterm babies.

• Future studies should investigate optimal doses of vitamin D based on babies' weights and report important outcomes such as bone health.

Why is vitamin D important for babies born early (preterm) or with a low birth weight?

Vitamin D helps the body absorb calcium from food, which is vital for bone development and strength. Without sufficient vitamin D, bones can become thin, brittle, or misshapen. This is called Rickets in children. Vitamin D is made in the skin when it is exposed to sunlight. It is also found in fish, meat and other animal-derived foods. Newborn babies may not receive exposure to sunlight, and babies fed human milk may not receive enough vitamin D. Sufficient vitamin D blood levels for babies are 50 nanomoles per litre (50 nmol/L) to 250 nmol/L; 'insufficiency' is under 50 nmol/L and 'deficiency' is under 30 nmol/L. Treatment is with supplements that can be swallowed or given by injection. Too much vitamin D (over 250 nmol/L) can cause unwanted effects, such as high calcium levels in the blood and kidney stones. Recommendations for vitamin D supplementation vary around the world.

What did we want to find out?

We wanted to find out the best dose or duration for giving vitamin D supplements to preterm babies and babies with a low birth weight. We were interested in whether vitamin D supplementation:

• reduces vitamin D deficiency or insufficiency;

• improves bone health;

• causes unwanted effects.

What did we do?

We searched for studies that compared vitamin D supplementation to no supplementation, or higher doses (more than 800 international units (IU)) to lower doses of vitamin D (200 IU to 800 IU) supplementation in preterm babies (born before 37 weeks of gestation) or babies with a low birth weight (less than 2500 g).

We compared and summarised the results of the studies, and rated how confident we are that the results are true and reliable, based on factors, such as study methods and sizes.

What did we find out?

We found 34 studies with 5012 babies.

Main resultsVitamin D supplementation versus no supplementation (11 studies, 1514 preterm babies)

Vitamin D supplementation probably reduces the risk of vitamin D deficiency (benefits 1 in every 4 babies supplemented; 4 studies, 385 babies), and may reduce the risk of vitamin D insufficiency (benefits 1 in every 3 babies supplemented; 4 studies, 385 babies) by the time babies are discharged from hospital. The effects on bone health and bone health blood markers were not reported.

Vitamin D supplementation versus no supplementation (1 study, 2079 near-term, low birthweight babies)

Vitamin D supplementation probably reduces vitamin D deficiency (benefits 1 in every 3 babies supplemented; 453 babies) and probably reduces vitamin D insufficiency (benefits 1 in every 3 babies supplemented; 453 babies) at six months of age. The effects on bone health and bone health blood markers, unhealthily high blood calcium and vitamin D levels were not reported.

Higher-dose (800 IU/day or more) versus lower-dose (200 to 800 IU/day) vitamin D supplementation (25 studies, 1546 preterm babies)

Higher doses of vitamin D probably reduce the risk of vitamin D deficiency (benefits 1 in every 8 babies supplemented; 11 studies; 672 babies), and may reduce the risk of vitamin D insufficiency (benefits 1 in every 4 babies supplemented; 11 studies; 683 babies) more than lower doses of vitamin D. However, higher doses probably lead to unhealthily high vitamin D levels (harms 1 in every 25 babies supplemented; 5 studies; 395 babies). Higher doses of vitamin D in preterm babies may enhance bone health by improving bone health blood markers. However, there may be little to no difference in the appearance of bones with X-rays (7 studies, 447 babies).

What are the limitations of the evidence?

There is not enough information about bone health and unwanted effects, including high blood calcium levels.

We based our judgement on the fact that the evidence is based on a few cases and the parents and assessors in the studies were aware of which treatment they were getting, and a few babies were not followed until the end of the study. We are not confident about other adverse effects from unhealthily high vitamin D levels, and higher blood calcium levels because of few events and small number of participants.

How up to date is this evidence?

The evidence is current to February 2026.

Key messages

• Telling people what treatment they will receive – rather than them not being told – improves recruitment.

• Telephoning people who don't respond to an initial postal invitation to join a trial improves recruitment when the initial recruitment rate is low.

• Tailored, user-tested information leaflets, sending letters about the importance of research, or providing a link to videos make little or no difference to recruitment.

What are research trials?

Research trials compare different approaches, such as treatments, programmes, or ways of delivering services. In health care, trials are essential to test new medicines and devices on human volunteers (‘trial participants’) to make sure they are safe and effective. However, finding and keeping trial participants is challenging. About half of all trials fail to recruit the number of people they need on time. Strategies to boost recruitment include changing trial methods and improving information for potential participants and how they are invited to take part.

What did we want to find out?

We wanted to find out which strategies encouraged more people to join research trials, and whether they:

• were good value for money (cost-effective);

• made any difference to whether people stayed in the trial until the end (retention); and

• had any effect on the diversity of the people and places involved.

What did we do?

We searched for studies that tested different recruitment strategies embedded within research trials. Potential participants were chosen by chance to receive different recruitment approaches, and the studies measured how many people joined the trial.

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

What did we find?

We found 91 studies, each involving between 37 and 30,000 participants, mostly conducted in the UK (46 studies) and USA (23 studies). All were in healthcare trials. Nearly all (99%) were carried out in high-income countries. Most studies gave little information about the people they recruited.

The studies tested 65 different recruitment strategies ranging from changes to trial methods to how people were approached and informed about taking part. Participants had different health concerns (e.g. cancer, surgery).

We are confident in the evidence for only 5 of the 65 strategies investigated, and we focus on these below.

Main results

Trial procedures

• Potential participants are more likely to join an ‘open-label’ trial, where they know their treatment, than a ‘blinded’ trial, where they do not know which treatment they will receive (3 trials, 9004 participants).

• For every 100 people invited, an open-label trial recruits 10 more participants.

• The trials involved mostly women in the UK and Estonia.

• There was no information about cost-effectiveness and retention.

Telephone reminders

• Telephoning people who have not responded to a postal invite improves recruitment (2 trials, 1450 people).

• Six more people take part if 100 people are called.

• Participants were aged 58 years on average and lived in Canada and Norway.

• There was no information on cost-effectiveness or retention.

Letters about the importance of research

• Sending letters about the importance of research before the trial invitation does not significantly improve recruitment (2 trials, 5376 participants).

• One more person joins if 100 people are sent a letter.

• This small gain was not good value, costing 2.08 pounds sterling (GBP) per additional participant recruited.

• The trials involved mostly older white people in the UK and Ireland.

QR code or link to videos alongside printed information leaflets

• Providing a QR code or link to videos alongside a printed information leaflet makes no difference to recruitment (7 trials, 11,612 participants) or retention (5 trials, 7403 participants).

• There is zero change per 100 people.

• This strategy was not cost-effective (GBP 0.78 more).

• The trials involved people in the UK.

Information leaflets

• Information leaflets developed with input from people similar to those being recruited make no difference compared to standard leaflets (6 trials, 27,805 participants).

• Both types of leaflet result in 7 in 100 people joining the trial.

• The trials involved people in the UK, mostly older women in one trial.

• There was no information on cost-effectiveness or retention.

What are the limitations of the evidence?

• Our confidence in all but the five strategies above is limited because they were tested in only one trial, the trials testing them had problems with their methods, or the results were very uncertain.

• We found cost information for only 8 strategies, and retention information for only 15 trials.

• Few trials reported information about participants' age, sex, gender, education level, and income level, so we are not sure how effective the strategies would be for different people.

• Most trials (75%) were carried out in the UK or USA, so our findings may not apply to healthcare systems in other parts of the world. We screened all non-English studies, none were eligible.

How up to date is this evidence?

This review updates our 2018 review. The evidence is current to February 2023.

Key messages

• It is unclear if medicines used to prevent bone loss (bisphosphonates) lower the risk of breaking a hip, backbone (spine), or other bones in men.

• These medicines probably do not cause more unwanted effects or serious health problems than dummy treatment (placebo) in men.

• Other medicines (parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) analogues, denosumab, and romosozumab) appear to show similar results, except we are very uncertain about the effects of PTH/PTHrP analogues on unwanted effects.

What is osteoporosis, and how is it related to fractures in men?

Bone loss (osteoporosis) is when bones become thin, fragile, and break (fracture) easily. Fractures commonly occur in the hip, backbone (spine), and other bones. These fractures often happen in older people after a fall from a standing height or less. Such fractures can lead to long-lasting pain, loss of independence, disability, and in some cases even death. Osteoporosis in men usually starts later in life and progresses more slowly than in women. Other risk factors for fractures such as balance, muscle strength, co-existing conditions, medications, and fall direction may also differ between men and women.

Doctors often use bone-strengthening medicines to help prevent fractures caused by minor falls or injuries. Common medicines include bisphosphonates (zoledronic acid, alendronate, risedronate, ibandronate), parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP) analogues, denosumab, or romosozumab. Most research on these medicines has been done in women, especially after menopause. Much less is known about the effects of these treatments in men who are at risk of fracture.

What did we want to find out?

We wanted to find out if these medicines reduce fractures of the hip, spine, or other bones, and if they cause unwanted effects in men at risk of fracture.

What did we do?

We searched for studies where men at risk of fracture were given bisphosphonates, PTH/PTHrP analogues, denosumab, or romosozumab compared with dummy treatment (placebo) or other treatments. 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 17 studies (4132 participants). The average age of participants ranged from 52 to 73 years. Two studies were conducted in Germany, four in the USA, one in Turkey, one in Taiwan, and nine studies were multinational.

Main results

Compared with placebo, at up to two years:

• 0.1% less people had a hip fracture when taking bisphosphonates, but the evidence is very uncertain (4 studies, 1635 people):

  • 0.2% of people had a hip fracture with bisphosphonate;

  • 0.3% of people had a hip fracture with placebo.

• 0.4% less people had symptomatic spine fractures when taking bisphosphonates, but the evidence is very uncertain (5 studies, 1876 people):

  • 0.4% of people had a symptomatic spine fracture with bisphosphonate;

  • 0.8% of people had a symptomatic spine fracture with placebo.

• 0.5% less people had other (not hip or spine) fractures when taking bisphosphonates, but the evidence is very uncertain (6 studies, 2043 people):

  • 1.6% of people had other fractures with bisphosphonate;

  • 2.1% of people had other fractures with placebo.

Bisphosphonates probably do not increase the risk of unwanted effects. 4.2% more people experienced unwanted effects with bisphosphonates compared to those taking a placebo (7 studies, 2548 people):

• 74.6% of people experienced unwanted effects with bisphosphonate;

• 70.4% of people experienced unwanted effects with placebo.

1.2% less people withdrew from the study because of unwanted effects with bisphosphonate compared to those taking a placebo, but the evidence is very uncertain (7 studies, 2548 people):

• 2.5% of people withdrew from the study because of unwanted effects with bisphosphonate;

• 3.7% of people withdrew from the study because of unwanted effects with placebo.

Bisphosphonates probably do not increase the risk of serious unwanted effects (6 studies, 2457 people). 1.4% less people experienced serious unwanted events with bisphosphonates compared to those taking a placebo:

• 27.2% of people experienced serious unwanted effects with bisphosphonate;

• 28.6% of people experienced serious unwanted effects with placebo.

Disability was not measured in any trial.

We found similar results for PTH or PTHrP analogues (4 studies, 569 people), denosumab (1 study, 240 people), and romosozumab (1 study, 244 people) compared with placebo.

What are the limitations of the evidence?

We have very low confidence in the effect of bisphosphonates on preventing fractures as there were few trials; the follow-up time was usually short (mostly two years or less); and there were few people with fractures in both study groups.

We have only moderate confidence in the effect of bisphosphonates on unwanted effects or serious unwanted effects because it was not clear if all studies had fully reported every event. We have very low confidence in the effect of bisphosphonates on study withdrawals due to unwanted effects, because in some studies it was not clear whether people withdrew because of unwanted effects or for other reasons.

How up to date is this evidence?

The evidence is current to October 2025.

Key messages

• People with stroke can safely take part in programmes of exercise that involve aerobic fitness training.

• Aerobic fitness training may improve fitness, reduce disability, increase walking speed, and improve balance at the end of the programme, but it is unclear if these are noticeable improvements.

• There is not enough evidence about the effects of aerobic training and further research is needed.

What is stroke?

A stroke occurs when the blood supply to part of the brain is interrupted, leading to damage in specific areas of the brain. The impact of stroke can be life-changing and varies depending on the severity of damage and where it occurs in the brain. As well as affecting the ability to move, stroke can impact thinking, feeling, and behaviour. These effects can persist throughout life after stroke. One physical impact of stroke is reduced aerobic fitness and muscle strength, which make physical activity and getting back to everyday activities more difficult. Low aerobic fitness could also be a risk for having another stroke.

What happens during rehabilitation after stroke?

After a stroke, many patients receive rehabilitation, for example, from a physiotherapist or other health professional, to help them overcome difficulties with everyday activities. Rehabilitation often includes different types of exercise. One type is aerobic (or 'cardiorespiratory') training, which involves continuous exercise that increases heart rate, which may increase the stamina needed for repetitive activities like walking.

What did we want to find out?

We wanted to find out if aerobic fitness training is beneficial at any time after stroke (whether in hospital or after going home). Specifically, we wanted to know whether aerobic training after stroke:

• is safe;

• improves physical fitness and movement (including walking and balance);

• changes how people feel (including depression and quality of life); and

• reduces the risk of another stroke.

What did we do?

We searched for studies that tested an aerobic training exercise programme for people after a stroke compared to usual care, no programme or a non-exercise programme. We only included studies if the exercise programme being tested was based only on aerobic training; we excluded studies that involved other types of exercise, such as muscle strength training.

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors like study methods and the number of people involved.

What did we find?

We found 53 studies involving 2672 people with stroke. Most of the study participants could walk. Thirty-seven of the studies were conducted in high-income countries. The average age of study participants was 61.9 years. Most studies took place either within three months of a stroke (19 studies) or at least six months after a stroke (29 studies). In 28 studies, the people in the aerobic exercise groups received more attention than those in the control groups.

In 49 studies, exercise sessions lasted between 20 and 60 minutes; in 48 studies, exercise frequency was 3 to 5 days a week. The programme was less than 12 weeks in 37 studies. Exercise intensity was reported as maximal heart rate, heart rate reserve (based on resting heart rate), or participants' ratings of perceived exertion.

Sixteen of the 53 studies followed up the people taking part in the studies. The length of follow-up ranged between 12 weeks and 12 months after the programme started. One study planned a six-month follow-up but did not report it.

Main results

• Aerobic exercise does not affect the number of deaths at the end of the programme (36 studies, 1563 participants) or at follow-up (10 studies, 713 participants).

• Aerobic exercise does not affect the number of second strokes at the end of the programme (8 studies, 544 participants) and probably does not affect them at follow-up (4 studies, 412 participants).

• We are very uncertain about the results for blood pressure at the end of the programme (9 studies, 535 participants) or at follow-up (3 studies, 155 participants).

• Aerobic exercise may cause small improvements in balance (18 studies, 772 participants), disability (17 studies, 1073 participants), aerobic fitness (13 studies, 608 participants) and comfortable walking speed (16 studies, 647 participants) at the end of the programme, but it is unclear if these changes are large enough to be meaningful for people with stroke. The results at follow-up are unclear; the aerobic fitness benefit may continue but may not be large enough to be meaningful for people with stroke (5 studies, 237 participants).

What are the limitations of the evidence?

• Most studies involved people who could walk; little is known about the many people with stroke who have more limited mobility.

• Most studies took place in high-income countries; little is known about people with stroke in other countries.

• There are many uncertainties and not enough evidence about the effects of aerobic training. Further research is needed.

How up to date is this evidence?

This review is one of three that update a previous single review on fitness training for stroke. The evidence is based on searches run up to April 2025.

Key messages

° Many NTCP models have been developed to predict unwanted effects following radiotherapy in head and neck cancer patients but most of them have not been sufficiently externally validated, that is, tested with patients who were not involved in the original model developmental study, to know how well they really predict the unwanted effects.

° For models tested in two or more studies in addition to their original model development studies, the quality of testing and reporting of their results was generally poor, so it is difficult to know how useful they might be.

° More and better designed studies are required to investigate this issue in the area of head and neck cancer.

How can we decide on the likelihood of having unwanted effects as a result of treatment?

The likelihood of having unwanted effects as a result of radiotherapy can be calculated by using so-called NTCP models. NTCP models calculate the risk of radiation-induced side effects based on information from the patient, their disease, and their treatment.

What did we want to find out?

Radiotherapy is the mainstay of treatment of patients with head and neck cancer. However, radiotherapy exposes healthy, sometimes crucial, parts of the head and neck region to radiation. This may result in damage to these normal organs, e.g. disturbed saliva production, which may have important consequences for the quality of life of head and neck cancer patients treated with radiotherapy. To reach an optimal balance between tumour control and preventing radiation-induced side effects, normal tissue complication probability (NTCP) models can be helpful. These models predict the risk of radiation-induced side effects based on information from the patient, their disease, and their treatment. There have been a substantial number of NTCP models for patients with head and neck cancer. We wanted to find out what the quality of study design, conduct, and analysis (i.e. risk of bias) is, and how well these models can predict the risk of radiation-induced side effects.

What did we do?

We searched for studies that developed and/or validated NTCP models in patients with head and neck cancer.

What did we find?

In most of the 617 models developed from 162,527 patients in 152 identified articles, the quality of the models was not sufficient; and it has not been investigated how well they perform in new patients for 78% of these models. For the remaining 22% of the models, 193 external validations were found in 48,852 patients from 39 articles. There were only ten models with two or more external validations. The models were able to distinguish patients with and without the outcome well, but it was often unclear whether their predictions were in line with what was observed, because the latter was not always assessed and/or reported. Overall, the quality of most of these studies was low.

How up to date is the review?

The evidence is current to 8th January 2024.

Key messages

• Iodine supplementation improves thinking ability (cognitive function) slightly and may have little to no effect on growth (weight) in children and adolescents. None of the studies reported unwanted effects.

• Iodine supplementation likely reduces the occurrence of insufficient production of thyroid hormones (hypothyroidism), and risk of infant death (mortality) in places with high infant mortality rates. We are unsure about its effect on reducing enlargement of the thyroid gland (goitre).

• Future studies should focus on areas or populations in which lack of iodine could be a problem, and include children of lower socioeconomic levels. They should look at higher doses of iodine given during longer periods of treatment and follow-up times.

What is iodine, and why is it important?

Iodine is a mineral used to make thyroid hormones, which are required for the normal development of the body and brain. Given its role in human development, it is especially important that children receive enough iodine. Lack of iodine (iodine deficiency) in children can lead to delayed growth and development of the central nervous system, intellectual disability, infant death, and enlargement of the thyroid gland (goitre).

The primary sources of iodine in the diet are iodised salt, seafood, grains from iodine-rich soils, and dairy products. Iodine supplementation can be given as combined iodine and plant-based oil (iodised oil), which is injected into a muscle only once or yearly, or as potassium iodide tablets, capsules, or drops, given in a low dose daily or weekly.

What did we want to find out?

We wanted to know whether iodine supplementation results in fewer children and adolescents having iodine deficiency disorders compared with placebo (dummy treatment). We also wanted to know if receiving iodine supplementation was associated with any unwanted effects.

What did we do?

We searched for studies comparing iodine supplementation to placebo in children and adolescents at risk of iodine deficiency. 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 eight studies (2528 people) that looked at the effects of preventive iodine supplementation in children and adolescents. The studies were conducted between 1982 and 2009 mainly in low‐income environs in Albania, Bangladesh, Colombia, Indonesia, Malawi, New Zealand, and Tanzania. The studies compared iodine supplementation by mouth (oral) (alone or with iron in one study) versus placebo.

Iodine supplementation versus placebo

• Iodine supplementation results in a slight increase in thinking ability (cognitive function) compared to placebo (1 study, 166 people).

• Iodine supplementation may result in little to no difference in children's weight compared to placebo (3 studies, 658 people).

• Iodine supplementation likely results in a large reduction in insufficient production of thyroid hormones (hypothyroidism) compared to placebo (1 study, 264 people).

• No study reported unwanted effects related to iodine or quality of life.

• Iodine supplementation likely reduces death due to any cause compared to placebo (1 study, 617 people).

• The evidence is very uncertain about the effect of iodine supplementation on the reduction of goitre (2 studies, 432 people). One study did not use robust methods. We removed it from our analyses and found that iodine likely results in a large reduction in goitre (1 study, 230 people).

Iodine plus iron supplementation versus placebo

• The evidence is very uncertain about the effect of iodine plus iron on weight (1 study, 146 people).

• No study reported cognitive function, hypothyroidism, unwanted effects, quality of life, death due to any cause, or goitre.

What are the limitations of the evidence?

Our confidence in the evidence ranged from high to very low. In cases where our confidence was limited, this was because:

• it is possible that people in the studies knew which treatment they were getting;

• the studies were done in different types of people;

• there are not enough studies to be certain about the results.

How up to date is this evidence?

The evidence is current to May 2025.