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.

Key messages

• HoLEP and the standard prostate operation (TURP) may relieve urinary symptoms and improve quality of life to a similar degree and with similar serious complications in the first year after surgery.

• HoLEP probably lowers the need for a blood transfusion compared to TURP, prostatectomy (removal of the prostate) and laser ablation (using a laser beam to destroy prostate tissue). For every 1000 men treated, about 36 fewer would need one.

• We don’t have enough evidence yet to say whether HoLEP is better for very large prostates or for people who take certain blood-thinning medicines.

What is benign prostatic hyperplasia?

The prostate is a small gland found only in men. It’s a non-cancerous condition where the prostate grows bigger as men get older, which can block urine flow. This is like a pipe getting narrower and harder to pee through.

How is benign prostatic hyperplasia treated?

Treatments include lifestyle changes, medicines, and surgeries. For a long time, the most common surgery was called transurethral resection of the prostate (TURP). In TURP, a doctor uses a small tool inserted through the urethra (the pee tube) to scrape away the extra prostate tissue. Today, doctors also use lasers to do this job. One type of laser surgery is called HoLEP.

What did we want to find out?

We wanted to know how HoLEP compares with other surgical options in terms of relief of symptoms, quality of life, and safety (unwanted effects).

What did we do?

We searched for studies where doctors compared HoLEP with other prostate surgeries. We looked at how well each surgery worked, how safe it was, and how quickly men recovered. We then summed all the results and assessed the reliability of each study.

What did we find?

We found 52 studies involving 6242 men who had prostate surgery. This summary focuses on studies comparing HoLEP with TURP — the standard prostate operation — in the first year after surgery, because this is the comparison the one most relevant to men choosing between operations. The average age of the men ranged from 65 to 74 years, and the average prostate size in the studies ranged from 30 cc to 142 cc. Studies took place in 11 countries.

• Symptoms and quality of life: HoLEP may relieve urinary symptoms (14 studies, 1666 people) and improve quality of life (6 studies, 876 people) to a similar extent as TURP. Any difference we found was too small to matter to men.

• Serious complications: HoLEP may have similar serious complications (10 studies, 1147 people) compared with TURP.

• Repeat surgery and erectile function: These are probably similar after both operations.

• Ejaculation: No study reported what happened to ejaculation after either operation, even though this matters a great deal to many men.

• Blood transfusion: HoLEP probably lowers the chance of needing a blood transfusion compared to most other surgeries. About 44 in every 1000 men need a transfusion after TURP, compared with about 8 in every 1000 after HoLEP (15 studies, 1755 people).

• We also compared HoLEP with other laser operations, other enucleation techniques, and open surgery, and examined results beyond one year. These results are reported in the full review.

What are the limitations?

• Study quality: Most studies had design problems — for example, it is impossible to mask surgeons and very challenging to mask patients as to which operation was performed, which can affect how results are measured and reported. Only a few studies had pre-registered plans, so some results may have been selectively reported. For these reasons, our confidence in many findings is low or very low.

• Short follow-up: Most studies only followed patients for up to 12 months. We do not know whether the benefits of HoLEP hold up over longer periods, or whether repeat surgery rates differ substantially in the long run.

• No study reported on ejaculatory function for any comparison. Given that roughly three out of four men experience retrograde ejaculation (dry orgasm) after HoLEP, this is an important gap. Data on urinary leakage (incontinence) after surgery were also not consistently reported.

• Surgeon experience: Most surgeons in the included studies were highly experienced with HoLEP. Actual results may differ where surgeons are still learning: complication rates continue to fall with experience, settling only after about 350 operations.

• Limited evidence for certain patient groups: We could not perform the planned analyses for men with very large prostates (≥ 80 mL) or those taking blood-thinning medicines, because too few studies included these patients. These are precisely the groups in whom HoLEP may offer the greatest advantage, so this is a particularly important gap.

• Fewer studies for some comparisons: Most evidence compared HoLEP with TURP; we are less certain about comparisons with laser ablation, alternative enucleation techniques, or open surgery.

How up-to-date is this review?

This review is up-to-date to April 08, 2026.

Key messages

• In adults with chronic hepatitis B, thymosin-alpha1 may reduce death from any cause and serious unwanted effects. We are less sure about its effects on well-being, hepatitis B-related illness or death, non-serious unwanted effects and liver health.

• Future studies should use more robust methods and include more people.

What is chronic hepatitis B?

Chronic hepatitis B is caused by infection with the hepatitis B virus (HBV). HBV attacks the liver, making it become inflamed – red, painful, and swollen. HBV infection can be short-term (acute) or long-term (chronic). Chronic HBV infection is when the condition lasts for more than six months. If not successfully treated, it may progress to chronic hepatitis, cirrhosis and other liver diseases, liver failure, cancer, and death.

What is thymosin-alpha 1?

Thymosin-alpha 1 is a substance made by a small gland in the chest called the thymus, which helps the body fight infections and disease. It may stop HBV from replicating and boost the body's immune system, helping it fight the virus. It is given as an injection under the skin.

What did we want to find out?

We wanted to know whether, in people with chronic hepatitis B, thymosin-alpha 1 is an effective treatment given alone, or with an additional treatment (called standard, regular, or supportive treatment), compared with placebo (dummy treatment) no treatment or the same additional treatment.

We were interested in whether thymosin-alpha 1:

• caused death for any reason

• caused serious unwanted effects (any event that led to death, disability or hospitalisation)

• improved people's well-being

• reduced HBV-related illness

• reduced risk of dying from chronic HBV infection

• reduced the risk of non-serious unwanted effects (events less serious than those above), and

• improved liver health.

What did we do?

We searched for studies that investigated thymosin-alpha 1 for people with chronic hepatitis B. Studies could include additional treatments as long as everyone in the study got the same additional treatment. Otherwise, people not receiving thymosin-alpha 1 received placebo or no treatment.

Studies could take place anywhere in the world. People in the studies could be men or women, and receive treatment by injection anywhere on the body and at any dose.

What did we find?

We found 10 studies involving 1349 adults with chronic hepatitis B. The studies investigated thymosin-alpha 1, given alone or with an additional treatment, compared with placebo (2 studies), no treatment (2 studies) or the same additional treatment (6 studies). The additional treatments were standard treatments for chronic HBV infection, including interferon, peginterferon, lamivudine, and tenofovir or entecavir.

The smallest study included 12 people, and the largest 690. The studies were funded by universities, the pharmaceutical industry, national bodies or research grants.

Thymosin-alpha 1 may:

• reduce the risk of death from any cause; in three studies, 14 of 460 people (3%) who received thymosin-alpha 1 died, compared with 26 of 447 people (5.8%) who received the control intervention from 6 months to 24 months after treatment;

• result in a small reduction in serious unwanted events; in five studies, 54 of 534 people (10.1%) who received thymosin-alpha 1 experienced a serious unwanted event, compared with 70 of 522 people (13.4%) who received the control intervention from 6 months to 24 months after treatment.

We are less certain that thymosin-alpha 1 may:

• make no difference to people's well-being five years after treatment (1 study, 161 people);

• make no difference to HBV-related illnesses. In three studies, 33 of 433 people (7.6%) who received thymosin-alpha 1 and 37 of 421 people (8.8%) who received the control intervention developed HBV-related illness from 6 to 24 months after treatment;

• reduce the risk of dying from chronic HBV. In three studies, 14 of 460 people (3%) who received thymosin-alpha 1 died from chronic HBV, compared with 26 of 447 people (5.8%) who received the control intervention up to 24 months after treatment;

• reduce the risk of non-serious unwanted effects; in five studies, 16 of 151 people (10.6%) who received thymosin-alpha 1 experienced a non-serious unwanted effect, compared with 32 of 149 people (21.5%) who received the control intervention from 12 months to 24 months after treatment;

• make no difference to improved liver health. In two studies, based on changes seen in liver samples, 146 of 358 people (40.8%) who received thymosin-alpha 1 had improved liver health compared with 163 of 344 people (47.4%) who received the control intervention from 12 months to 24 months after treatment.

What are the limitations of the evidence?

All 10 studies had problems with design and methods. Overall, we have little confidence in the results because only a few studies provided information on the outcomes we were interested in, results varied across studies, and many studies included a small number of participants.

How up-to-date is this evidence?

The evidence is current to June 2026.

Key messages

• The effects of hormone therapy on women’s long-term health differ depending on whether they take combined hormone therapy (both oestrogen and progestogen) or oestrogen alone.
• We suggest using caution when considering the results of this review, given the evolution in the doses and methods for taking hormone therapy over time. Findings summarised here come from studies that gave hormone therapy as tablets taken by mouth.
• Future studies could explore the long-term effects of hormone therapy in women who are under 50 years, or whose ovaries have stopped working because of medical treatment.

What are menopause and perimenopause?

Menopause occurs naturally (usually between 44 and 55 years) when the ovaries stop releasing eggs and reduce (almost stop) hormone production. Menopause is diagnosed when these changes lead to 12 consecutive months without a menstrual period. Menopause also occurs after surgery to remove both ovaries, and does not require this 12-month timeframe.

Perimenopause is the transitional phase before menopause, when hormone levels decline and periods become irregular. It may last several years and causes symptoms like hot flushes, night sweats and mood changes.

Lower hormone levels may affect women's heart, blood vessels and bones, increasing the risk of high cholesterol, weight and fat changes, high blood pressure, diabetes, heart disease, stroke, osteoporosis and reduced strength or mobility.

What is hormone therapy?

Hormone therapy uses oestrogen, with or without another hormone called progestogen, to relieve menopause symptoms. Women without a womb (uterus) can take oestrogen alone, while those with a womb need both (oestrogen and progestogen) to protect against cancer of the womb lining (endometrial cancer).

Oestrogen may be given orally or through the skin (transdermally), and progestogen may be given orally, through the vagina (transvaginally) or by using an intrauterine device (T-shaped device inside the womb). Combined hormone therapy can be taken daily or cyclically (oestrogen is given daily and progestogen is given for part of the month, producing withdrawal vaginal bleeds).

What did we want to find out?

We wanted to find out if long-term use of hormone therapy affects women’s health in the long term.

What did we do?

We searched for studies that compared menopausal women taking hormone therapy for at least one year to those taking an inactive 'dummy' medicine (placebo). 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 24 studies involving 45,660 participants. Most data came from two large, high-quality studies conducted during the 1990s and reported in the early 2000s. The results presented below are drawn from one of those studies. We present full results in the main review.

Combined continuous hormone therapy compared to placebo

Based on evidence from one study in 16,608 women that measured outcomes at roughly 5.5 years of follow-up, combined continuous hormone therapy probably:

• made little or no difference to the risk of having a heart attack or developing lung cancer;
• increased the chance of developing breast cancer (from about 19 to 24 women in every 1000);
• reduced the risk of bone fractures (from about 111 to 87 women in every 1000).

Combined continuous hormone therapy may have increased the chances of having:

• a stroke (from about 13 to 18 women in every 1000);
• a blood clot in a vein (from about 10 to 20 women in every 1000);
• gallbladder disease requiring surgery (from about 16 to 27 women in every 1000).

Oestrogen-only therapy compared to placebo

Based on evidence from one study in 10,739 women who had undergone a hysterectomy (surgery to remove the womb) that measured outcomes at 7 years of follow-up, oestrogen-only hormone therapy probably:

• made little or no difference to the risk of having a heart attack, a blood clot in a vein, or developing breast cancer;
• reduced the chance of having a bone fracture (from about 141 to 103 women in every 1000);
• increased the chance of having a stroke (from about 24 to 32 women in every 1000) and gallbladder disease requiring surgery (from about 27 to 47 women in every 1000).

Oestrogen-only hormone therapy may have made little or no difference to the risk of developing lung cancer.

We did not have enough data to assess the risk of long-term hormone therapy use in women younger than 50 years.

What are the limitations of the evidence?

Only about 30% of the women were 50 to 59 years old at baseline, the age group most likely to consider hormone therapy for hot flushes and night sweats. In addition, hormone therapy has changed over time, with new ways to take it, different hormone types, and updated doses. The study providing most of the data gave women hormone therapy in pill form, which may have different risks to the types currently used in clinical practice.

How current is this evidence?

The evidence is current to September 2024.

Key messages

Magnesium sulphate given to women at risk of preterm birth for protecting their babies' brains reduces cerebral palsy, and the combined outcome of death or cerebral palsy, in their children up to two years of age, when compared with placebo.

Future research in this area should focus on the effects of treatment:

• on children when they are adolescents and adults; and

• for different groups of women at risk of preterm birth, and with different ways of giving magnesium sulphate.

What is magnesium sulphate?

Magnesium sulphate is a common medicine used across the world for different complications in pregnancy.

Why is this important for women at risk of preterm birth and their babies?

Babies born early (preterm, before 37 weeks of pregnancy) have a higher risk of complications including death and disabilities, such as cerebral palsy. In recent years, magnesium sulphate has been given to women who are likely to have their babies preterm (because of spontaneous preterm labour, or a medical indication to plan an induction of labour or caesarean birth early) to help protect their babies' brains and prevent these complications.

What did we want to find out?

We wanted to find out if magnesium sulphate is better than placebo (a 'dummy' treatment that does not contain any medicine but appears identical to the medicine being tested) at protecting the brains of babies likely to be born preterm.

We were interested in the effect of magnesium sulphate on important outcomes, including: death (of the babies, or later as children), cerebral palsy, and major 'neurodevelopmental disability' (which might include serious outcomes like cerebral palsy, blindness, deafness, or global cognitive or intellectual impairment). We were also interested in the effect on important outcomes for women, including serious complications of magnesium sulphate (death, respiratory or cardiac arrest), and stopping treatment because of side effects.

What did we do?

We searched for studies that looked at whether magnesium sulphate caused benefits or harms for women and their preterm babies when compared to placebo or no treatment. We compared and summarised results and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found six studies involving 5917 women at less than 34 weeks of pregnancy and their 6759 babies. The studies were all conducted in high-income countries. The included studies compared magnesium sulphate with placebo.

Main results

Compared with placebo, magnesium sulphate in women at risk of having their babies preterm:

• reduces cerebral palsy (evidence from 6 studies with 6107 children) and the combined outcome of death or cerebral palsy (6 studies, 6481 children) for children up to two years of age;

• probably makes little to no difference in death (6 studies, 6759 children), major neurodevelopmental disability (1 study, 987 children), or the combined outcome of death or major neurodevelopmental disability (3 studies, 4279 children), for children up to two years of age;

• may make little to no difference in the above-mentioned outcomes for children at early school age;

• may make little to no difference in serious complications of treatment for women (4 studies, 5300 women), but probably increases women stopping treatment because of side effects (3 studies, 4736 women).

What are the limitations of the evidence?

We are confident in our finding that magnesium sulphate reduces cerebral palsy, and the combined outcome of death or cerebral palsy, in children up to two years of age.

We have little confidence in the evidence for outcomes of children at school age, as studies could not provide data for all children, and there are not yet enough studies/data to be certain about the results.

We have little confidence in our finding that magnesium sulphate makes little to no difference in serious complications of treatment for women, as there was only one complication reported in one study. We have moderate confidence in our findings that magnesium sulphate probably increases women stopping treatment because of side effects, as the findings differed across studies, probably because of different decision-making processes for stopping treatment.

The results of further research for the outcomes in which we have limited confidence could differ from the results of this review.

How up-to-date is this evidence?

The evidence is current to 17 March 2023.

Key messages

• Multisensory stimulation (the stimulation of more than one sense at a time) may support growth in preterm infants by increasing weight gain before discharge from the hospital. However, it is unclear whether it improves longer-term developmental outcomes or reduces the risk of death, as the available evidence is limited and uncertain.

• When compared with stimulation of a single sense (touch alone), it is uncertain whether multisensory stimulation is better than touch alone at increasing weight gain during the intervention.

What is multisensory stimulation, and how does it work?

Multisensory stimulation means giving premature babies experiences that activate two or more of their senses. The senses involved and the types of stimulation used include the sense of:

• hearing — a parent’s voice, singing, or calming music;

• touch — massage or passive movements;

• smell and taste — a mother’s scent or breast milk;

• balance — gentle rocking or changing the baby's position;

• sight — soft, cycled lighting and simple shapes, colors, or moving patterns.

During the newborn period, the brain grows very quickly. Providing positive sensory experiences at this time may help premature babies in several ways, such as supporting their memory, helping them regulate emotions, and improving early learning and development.

What did we want to find out?

We wanted to find out whether multisensory stimulation compared with single‑sense stimulation or standard care helps premature babies survive, grow, stay healthy, and develop well. Specifically, we wanted to find out whether multisensory stimulation might:

• reduce the number of babies with severe developmental problems at 18 to 24 months' age, such as cerebral palsy, delay in development, limitations in mental abilities, blindness, or deafness;

• reduce the number of babies who die during the newborn period or before hospital discharge;

• increase the amount of weight the infants gained by the time they left the hospital.

We also looked at other important measures of the babies’ health, including:

• how long they stayed in the hospital or in the neonatal intensive care unit (NICU);

• how long it took before they could feed fully by mouth;

• how many days they needed breathing support.

What did we do?

We searched for studies in which multisensory stimulation began before the baby was discharged from the hospital after birth, and which compared multisensory stimulation with:

• no intervention or standard care;

• single-sense stimulation.

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

What did we find?

We included 19 studies (1544 premature babies). Eighteen of these studies compared multisensory stimulation with standard care, and one study compared multisensory stimulation with a single‑sense intervention (touch only).

In 10 studies, the main goal was to examine how multisensory stimulation affects babies’ brain and behavioral development.

The remaining nine studies focused on weight gain during the intervention, weight gain prior to hospital discharge, length of stay in the NICU, total length of hospital stay, time until the baby could feed fully by mouth, number of days the baby needed breathing support, or a combination of these measures.

We also found 13 ongoing studies and 4 studies that have not yet been fully assessed. They may give us more useful information in the future.

Main results

None of the studies that compared multisensory stimulation with no intervention reported on the critical outcome major developmental disability at 18 to 24 months' corrected age. Only one study assessed a related outcome, cerebral palsy at 12 months. Because this study was very small, the evidence is very uncertain about whether multisensory stimulation modifies the risk of cerebral palsy.

Multisensory stimulation may result in little or no difference in death before hospital discharge, although it was reported in only one large study. It may increase total weight gain prior to discharge, but the observed effect is small, and its clinical significance remains uncertain.

Compared with single-sense stimulation (touch), we could not tell whether multisensory stimulation helped babies gain more weight during the intervention. The only study we found comparing a multi- to single-sensory intervention did not report the critical outcomes, such as major developmental problems at 18 to 24 months' corrected age, death during the first hospital stay, or total weight gain prior to discharge.

What are the limitations of the evidence?

We have limited confidence in these findings because many of the studies were small or not well-designed. Several studies did not report the outcomes we were most interested in or did not provide enough data for us to analyze. Because of these limitations, the true effects of multisensory stimulation may be different from what we found.

How up-to-date is this evidence?

The evidence is up-to-date to 28 November 2025.