What is Lung Cancer?

Cancer is a class of diseases characterized by out-of-control cell growth, and lung cancer occurs when this uncontrolled cell growth begins in one or both lungs. Rather than developing into healthy, normal lung tissue, these abnormal cells continue dividing and form lumps or masses of tissue called tumors. Tumors interfere with the main function of the lung, which is to provide the bloodstream with oxygen to be carried to the entire body. If a tumor stays in one spot and demonstrates limited growth, it is generally considered to be benign.

More dangerous, or malignant, tumors form when the cancer cells migrate to other parts of the body through the blood or lymph system. When a tumor successfully spreads to other parts of the body and grows, invading and destroying other healthy tissues, it is said to have metastasized. This process itself is called metastasis, and the result is a more serious condition that is very difficult to treat.

Lung cancer is called "primary" if the cancer originates in the lungs and "secondary" if it originates elsewhere in the body but has metastasized to the lungs. These two types are considered different cancers from diagnostic and treatment perspectives.

In 2007, about 15% of all cancer diagnoses and 29% of all cancer deaths were due to lung cancer. It is the number one cause of death from cancer every year and the second most diagnosed after breast and prostate cancers (for women and men, respectively). Lung cancer is usually found in older persons because it develops over a long period of time.

How is lung cancer classified?

Lung cancer can be broadly classified into two main types based on the cancer's appearance under a microscope: non-small cell lung cancer and small cell lung cancer. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers, while small cell lung cancer accounts for the remaining 20%.

NSCLC can be further divided into four different types, each with different treatment options:

• Squamous cell carcinoma or epidermoid carcinoma. As the most common type of NSCLC and the most common type of lung cancer in men, squamous cell carcinoma forms in the lining of the bronchial tubes.
• Adenocarcinoma. As the most common type of lung cancer in women and in nonsmokers, adenocarcinoma forms in the mucus-producing glands of the lungs.
• Bronchioalveolar carcinoma. This type of lung cancer is a rare type of adenocarcinoma that forms near the lungs' air sacs.
• Large-cell undifferentiated carcinoma. A rapidly growing cancer, large-cell undifferentiated carcinomas form near the outer edges or surface of the lungs.

Small cell lung cancer (SCLC) is characterized by small cells that multiply quickly and form large tumors that travel throughout the body. Almost all cases of SCLC are due to smoking.

What causes cancer?

Cancer is ultimately the result of cells that uncontrollably grow and do not die. Normal cells in the body follow an orderly path of growth, division, and death. Programmed cell death is called apoptosis, and when this process breaks down, cancer begins to form. Unlike regular cells, cancer cells do not experience programmatic death and instead continue to grow and divide. This leads to a mass of abnormal cells that grows out of control.

Lung cancer occurs when a lung cell's gene mutation makes the cell unable to correct DNA damage and unable to commit suicide. Mutations can occur for a variety of reasons. Most lung cancers are the result of inhaling carcinogenic substances.

Carcinogens

Carcinogens are a class of substances that are directly responsible for damaging DNA, promoting or aiding cancer. Tobacco, asbestos, arsenic, radiation such as gamma and x-rays, the sun, and compounds in car exhaust fumes are all examples of carcinogens. When our bodies are exposed to carcinogens, free radicals are formed that try to steal electrons from other molecules in the body. These free radicals damage cells and affect their ability to function and divide normally.

About 87% of lung cancers are related to smoking and inhaling the carcinogens in tobacco smoke. Even exposure to second-hand smoke can damage cells so that cancer forms.

Genes

Cancer can be the result of a genetic predisposition that is inherited from family members. It is possible to be born with certain genetic mutations or a fault in a gene that makes one statistically more likely to develop cancer later in life. Genetic predispositions are thought to either directly cause lung cancer or greatly increase one's chances of developing lung cancer from exposure to certain environmental factors.

How does lung cancer develop? - video

A short video explaining how lung cancer develops. Video by eHow.

What are the symptoms of lung cancer?

Cancer symptoms are quite varied and depend on where the cancer is located, where it has spread, and how big the tumor is. Lung cancer symptoms may take years before appearing, usually after the disease is in an advanced stage.

Many symptoms of lung cancer affect the chest and air passages. These include:

• Persistent or intense coughing
• Pain in the chest shoulder, or back from coughing
• Changes in color of the mucus that is coughed up from the lower airways (sputum)
• Difficulty breathing and swallowing
• Hoarseness of the voice
• Harsh sounds while breathing (stridor)
• Chronic bronchitis or pneumonia
• Coughing up blood, or blood in the sputum

If the lung cancer spreads, or metastasizes, additional symptoms can present themselves in the newly affected area. Swollen or enlarged lymph nodes are common and likely to be present early. If cancer spreads to the brain, patients may experience vertigo, headaches, or seizures. In addition, the liver may become enlarged and cause jaundice and bones can become painful, brittle, and broken. It is also possible for the cancer to infect the adrenal glands resulting in hormone level changes.

As lung cancer cells spread and use more of the body's energy, it is possible to present symptoms that may also be associated with many other ailments. These include:

• Fever
• Fatigue
• Unexplained weight loss
• Pain in joints or bones
• Problems with brain function and memory
• Swelling in the neck or face
• General weakness
• Bleeding and blood clots

How is lung cancer diagnosed and staged?

Physicians use information revealed by symptoms as well as several other procedures in order to diagnose lung cancer. Common imaging techniques include chest X-rays, bronchoscopy (a thin tube with a camera on one end), CT scans, MRI scans, and PET scans. Physicians will also conduct a physical examination, a chest examination, and an analysis of blood in the sputum. All of these procedures are designed to detect where the tumor is located and what additional organs may be affected by it.

Although the above diagnostic techniques provided important information, extracting cancer cells and looking at them under a microscope is the only absolute way to diagnose lung cancer. This procedure is called a biopsy. If the biopsy confirms lung cancer, a pathologist will determine whether it is non-small cell lung cancer or small cell lung cancer.

After a diagnosis is made, an oncologist will determine the stage of the cancer by finding out how far the cancer has spread. The stage determines which choices will be available for treatment and informs prognosis. The most common cancer staging method is called the TNM system. T (1-4) indicates the size and direct extent of the primary tumor, N (0-3) indicates the degree to which the cancer has spread to nearby lymph nodes, and M (0-1) indicates whether the cancer has metastasized to other organs in the body. A small tumor that has not spread to lymph nodes or distant organs may be staged as (T1, N0, M0), for example.

For non-small cell lung cancer, TNM descriptions lead to a simpler categorization of stages. These stages are labeled from I to IV, where lower numbers indicate earlier stages where the cancer has spread less. More specifically:

• Stage I is when the tumor is found only in one lung and in no lymph nodes.
• Stage II is when the cancer has spread to the lymph nodes surrounding the infected lung.
• Stage IIIa is when the cancer has spread to lymph nodes around the trachea, chest wall, and diaphragm, on the same side as the infected lung.
• Stage IIIb is when the cancer has spread to lymph nodes on the other lung or in the neck.
• Stage IV is when the cancer has spread throughout the rest of the body and other parts of the lungs.

Small cell lung cancer has two stages: limited or extensive. In the limited stage, the tumor exists in one lung and in nearby lymph nodes. In the extensive stage, the tumor has infected the other lung as well as other organs in the body.

Screening for lung cancer - video

A video tutorial discussing Lung Cancer and screening. Video by OncologyPodCasting.

How is lung cancer treated?

Lung cancer treatments depend on the type of cancer, the stage of the cancer (how much it has spread), age, health status, and additional personal characteristics. As there is usually no single treatment for cancer, patients often receive a combination of therapies and palliative care. The main lung cancer treatments are surgery, chemotherapy, and/or radiation. However, there also have been recent developments in the fields of immunotherapy, hormone therapy, and gene therapy.

Surgery

Surgery is the oldest known treatment for cancer. If a cancer is in stage I or II and has not metastasized, it is possible to completely cure a patient by surgically removing the tumor and the nearby lymph nodes. After the disease has spread, however, it is nearly impossible to remove all of the cancer cells.

Lung cancer surgery is performed by a specially trained thoracic surgeon. After removing the tumor and the surrounding margin of tissue, the margin is further studied to see if cancer cells are present. If no cancer is found in the tissue surrounding the tumor, it is considered a "negative margin." A "positive margin" may require the surgeon to remove more of the lung tissue.

Lung cancer surgery can be curative or palliative. Curative surgery aims to cure a patient with early stage lung cancer by removing all of the cancerous tissue. Palliative surgery aims to remove an obstruction or open an airway, making the patient more comfortable but not necessarily removing the cancer.

Surgery carries side effects - most notably pain and infection. Lung cancer surgery is an invasive procedure that can cause harm to the surrounding body parts. Doctors will usually provide several options for alleviating any pain from surgery. Antibiotics are commonly used to prevent infections that may occur at the site of the wound or elsewhere inside the body.

Radiation

Radiation treatment, also known as radiotherapy, destroys or shrinks lung cancer tumors by focusing high-energy rays on the cancer cells. This causes damage to the molecules that make up the cancer cells and leads them to commit suicide. Radiotherapy utilizes high-energy gamma-rays that are emitted from metals such as radium or high-energy x-rays that are created in a special machine. Radiation can be used as the main treatment for lung cancer, to kill remaining cells after surgery, or to kill cancer cells that have metastasized.

Early radiation treatments caused severe side-effects because the energy beams would damage normal, healthy tissue, but technologies have improved so that beams can be more accurately targeted. Radiation oncologists can focus the radiation in precise locations in the body for certain lengths of time, reducing the risk of damage to surrounding healthy tissue. Treatments occur intermittently over weeks or months depending on the size and extent of the tumor, the dosage of radiation, and how much damage is being done to noncancerous tissue.

Common side effects of radiation therapy include fatigue, nausea, loss of appetite, hair loss, and skin affectations that cause skin to become dry, irritated, and sensitive.

Chemotherapy

Chemotherapy utilizes strong chemicals that interfere with the cell division process - damaging proteins or DNA - so that cancer cells will commit suicide. These treatments target any rapidly dividing cells (not just cancer cells), but normal cells usually can recover from any chemical-induced damage while cancer cells cannot. Chemotherapy is considered systemic because its medicines travel throughout the entire body, killing the original tumor cells as well as cancer cells that have spread throughout the body.

A medical oncologist will usually prescribe chemotherapy drugs for lung cancer to be taken intravenously, but there are also drugs available in tablet, capsule, and liquid form. Chemotherapy treatment occurs in cycles so the body has time to heal between doses, and dosages are determined by the type of lung cancer, the type of drug, and how the person responds to treatment. Medicines may be administered daily, weekly, or monthly, and can continue for months or even years.

Combination therapies often include multiple types of chemotherapy, and chemotherapy is also given as adjuvant therapy as a complement to surgery and radiation. Adjuvant therapy is designed to reduce the risk of cancer recurrence after surgery and killing any cancer cells that exist after surgery. Chemotherapy can be given before surgery, called neo-adjuvant therapy, to shrink tumors and to make surgery more successful.

Chemotherapy carries several common side effects, but they depend on the type of chemotherapy and the health of the patient. These include nausea and vomiting, appetite loss, diarrhea, hair loss, fatigue from anemia, infections, bleeding, and mouth sores. Many of these side effects are only temporarily felt during treatment, and several drugs exist to help patients cope with the symptoms.

Other Treatments

Researchers continue to search for ways to improve lung cancer treatments and find new methods of treating the disease. Targeted therapies are designed to only treat cancer cells while leaving alone normal and healthy lung cells. These include monoclonal antibodies that travel directly to the cancer cells and release drugs or radiation, anti-angiogenesis agents that interfere with the blood supply creation mechanism of cancer cells, and growth factor inhibitors that block the effects of growth factors and disallow the cancerous cells to grow. There is also some research in the area of lung cancer vaccines that first transform cancer cells so they are no longer cancerous. However, the cells will exist such that the body's immune system can recognize the cancerous cells as foreign and attack them. These targeted therapies are also called immunotherapies because the treatment tweaks the body's natural immune responses.

How can lung cancer be prevented?

Cancers that are closely linked to certain behaviors are the easiest to prevent. For example, choosing not to smoke tobacco or drink alcohol significantly lowers the risk of several types of cancer - most notably lung, throat, mouth, and liver cancer. Even if you are a current tobacco user, quitting can still greatly reduce your chances of getting cancer. The most important preventive measure you can take to avoid lung cancer is to quit smoking.

Quitting smoking will also reduce your risk of several other types of cancer including esophagus, pancreas, larynx, and bladder cancer. If you quit smoking, you will usually reap additional benefits such as lower blood pressure, enhanced blood circulation, and increased lung capacity.

Exposure to tobacco smoke is not the only risk factor for lung cancer though. Those who have come into contact with asbestos, radon, and secondhand smoke also have an increased risk of developing lung cancer. In addition, having a family member who developed lung cancer without being exposed to carcinogens could mean that you have a genetic predisposition for developing the disease, increasing your overall risk.

Screening techniques are designed to find cancer at the earliest stage so that the most treatment options are available, increasing survival rates and avoiding highly invasive procedures. Most lung cancers are detected in the late stages of the disease after they have spread and are harder to treat. Although there currently do not exist approved screening tests for lung cancer that improve survival or detect localized disease, there is promising research underway. Advocates of screening recommend that certain high risk groups be screened. This includes persons age 60 or older with a history of smoking, previous lung tumors, or chronic obstructive pulmonary disease (COPD). Possible lung cancer screening tests include analysis of sputum cells, fiberoptic examination of bronchial passages (bronchoscopy), and low-dose spiral CT scans.

Lower IQ Linked To Higher Attempted Suicide Risk, Large Swedish Study

A large scale study of over 1.1 million men living in Sweden that spanned nearly a quarter of a century found a link between lower IQ measured in early adulthood and higher risk of attempted suicide later in life.

The prospective cohort study was the work of Dr Finn Rasmussen, a professor in the Department of Public Health Sciences at Karolinska Institute, Stockholm, Sweden, and colleagues from the UK and Australia. They wrote a paper about it published in the 3 June online issue of the British Medical Journal, BMJ.

As well as exploring the links between early IQ scores and attempted suicide, Rasmussen and colleagues wanted to see if psychosis made a difference and also how variations in early IQ might relate to methods of attempted suicide.

Described as the largest study of its kind, they examined the medical records of nearly 1,109,500 men aged between 16 and 57 years living in Sweden.

Of these Rasmussen and colleagues found that nearly 18,000 (1.6 per cent) had been admitted to hospital at least once for attempting suicide during 24 years of follow up (after having IQ tested).

They found that men with the lowest early adulthood IQ scores were almost nine times more likely to attempt suicide then those with the highest, and there was a stepwise increase in risk across the full IQ range, which was "evident for attempted suicide by any means and for seven specific methods".

The authors wrote that while adjustment for "childhood and adult socioeconomic status and, to a greater extent, education led to a reduction in magnitude", the links remained strong.

However, for men who had been diagnosed with psychosis before attempting suicide, a separate analysis showed there was no such link between IQ level and attempted suicide risk.

They concluded that "low IQ scores in early adulthood were associated with a subsequently increased risk of attempted suicide in men free from psychosis," and recommended looking more closely at the underlying mechanisms to see if they reveal opportunities to intervene and reduce rates of suicide among men.

Speculating on the reasons behind the link, they suggested perhaps because people with lower IQ tend to have lower socioeconomic status and income, they could face more social and financial hardship, leading to their having more suicidal thoughts and behaviours.

They also mentioned that unhealthy lifestyle (eg binge drinking) has also been linked with lower IQ, and this could also affect frequency of suicidal thinking, plus other studies have also linked lower IQ with lower problem solving skills, and this could affect resilience to stress.

Another possibility is some research suggests that exposure to violence in childhood, either as a victim or a witness, can hamper IQ development as well as influence future suicide risk.

"Psychosis alters association between IQ and future risk of attempted suicide: cohort study of 1 109 475 Swedish men."
G David Batty, Elise Whitley, Ian J Deary, Catharine R Gale, Per Tynelius, Finn Rasmussen.
BMJ 2010;340:c2506 
Published online 3 June 2010
DOI:10.1136/bmj.c2506

Source: BMJ.

Written by: Catharine Paddock, PhD 
Copyright: Medical News Today 

The Rhesus Factor

GENOTYPING

First of all, the terms Rhesus positive and Rhesus negativeare now, more frequently, being described as Rh(D) positive and Rh(D) negative. This section should hopefully explain why the transition has become necessary and, also, provide basic information about the Rhesus factor. Although the initial thought of reading through this may seem daunting, you may prefer to come back to it if you encounter any information which needs reinforcing. Alternatively, for an adequate understanding that can be applied to the other sections, skip to the end of the detailed section and read the simplified explanation below.

Detailed Explanation:

We all inherit a set of three Rhesus (Rh) genes from each parent called a haplotype. You may have heard of the c, d, e, C, D and E genes. The upper case letters denote Rh positive genes and the lower case, negative and we inherit either a positive or negative of each gene from each parent (eg. CDe/cde, cdE/cDe etc.). This means that we then possess two of each gene and can pass either to ouroffspring.

If a person is tested Rh positive, their blood is said to contain the Rhesus factor - if they are tested negative it does not. A person possessing one or more positive Rh genes (C, D or E), anywhere in their inherited haplotypes, has inherited the Rh factor (eg. cdE/De, cde/cDe etc.) and they are tested Rh positive - only a person with a genotype of cde/cde is truly Rh negative.

In this respect, it is now common practice to refer only to the D gene when determining the Rh factor of a person`s blood. The term now used is `Rh(D)` instead of just `Rhesus`. This ensures that we concentrate solely on the D gene, or lack of it, as Rh(D) positive cells contain a substance (D antigen) capable of stimulating Rh(D)negative blood into producing harmful antibodies. These antibodies destroy (hemolyze) red cells containing the D antigen (Rh(D) positive cells). The c, e, C and E genes are of little importance here, as cases where antibodies have been produced against them are very rare, although there have been instances where this has occurred and treatment has become necessary. Information about them is still found in pregnancy booklets.

This may help to explain why the harmful antibody produced by a Rh(D)negative woman`s immune systemagainst Rh(D) positive cells is called `anti-D` (anti-Rh(D) - also the name of the injection given to a woman at delivery - see `The Purpose of Anti-Rh(D) Injections`). This injection is sometimes also referred to as RhoGAM or Anti-D Immunoglobulin.

PLEASE NOTE: A Rh(D) positive woman would never produce an antibody against a Rh(D) negative child, as positive blood does not produce `anti-d` - there is no anti-Rh(d).

A person is Rh(D) negative if they have inherited a d gene from each parent (d/d).

A person is Rh(D) positive if they have inherited either of the following: 

- a D gene from each parent (D/D)

- a D from one parent and a d from the other (D/d or d/D)

Therefore, it is possible to have a Rh(D) negative child if the mother is Rh(D) negative and the father Rh(D) positive. The father may have inherited both a D and d and it is possible that the baby could inherit the negatived gene from him. As Rh(D) negative woman definitely possess two d genes, the baby would inherit one of these from her - this combination would produce a negative child (d/d).

If the father possesses two D genes, the baby will definitely inherit a positive from him, together with the Rh(D) negative gene (d) from the mother. This combination will produce a Rh(D) positive child.

PLEASE NOTE: If a Rh(D) negative woman is absolutely certain that her partner is also Rh(D) negative, they will surely produce Rh(D) negative offspring and the baby will not be affected by Rh(D) problems, even if the mother already carries Rh(D) antibodies from a previous pregnancyor miscarriage with another partner or as a result of a transfusion using positive blood cells.

Even though both the d and D gene are referred to here, the term Rh(D) does indicate that the d gene is not really the issue here - the test performed is to determine the presence or lack of the D gene:

If a blood test shows that you do not possess the D gene, you are described as Rh(D) negative.

If this gene is found to be present, you will be described as Rh(D) positive.

So, for example:

If your blood type is B Rhesus positive (B+), the more accurate way of describing this is B Rh(D) positive (D gene is present).

If your blood type is A Rhesus negative (A-), it would be described as A Rh(D) negative (D gene is not present).

So, we can now see that if you possess the D gene and are, therefore, Rh(D) positive, your blood will contain the D antigen which stimulates Rh(D) negative blood into producing antibodies (anti-Rh(D)) against it.

At the risk of complicating this subject even more - a man who has inherited both positive factors (D/D) would be described as being Homozygous - meaning that every one of his sperms must contain the D gene. If a he has both (D/d or d/D) he would be described as being Heterozygous - meaning that 50% of his sperms contain the D gene and 50% contain d.

Simple Explanation:

Whatever our blood type (ie. A, B AB, O), we all have two Rhesus genes, called D or d, depending on whether we are Rhesus positive or negative and babies inherit one of these from each parent.

A person is Rh(D) negative if they have inherited a d gene from each parent (d/d)

A person is Rh(D) positive if they have inherited either of the following:

- a D gene from each parent (D/D)

- a D from one parent and a d from the other (D/d or d/D)

This is why it is possible to have a Rh(D) negative child if the mother is Rh(D) negative and the father Rh(D) positive. If the father has both a negative and a positive gene, the baby may inherit this negative gene and, as all Rh(D) negative women have two negative genes, the baby will definitely inherit a negative from her.

PLEASE NOTE: If a negative woman is absolutely sure that her partner is Rh(D) negative, they will surely produce Rh(D) negative offspring and no harm can come to the baby from any Rhesus antibody the mother`s blood may contain, even if she had already developed Rhesus Iso-immune disease before the pregnancy.

Rh(D) positive blood contains the D antigen which stimulates Rh(D) negative blood into producing antibodies against it. Anti-Rh(D) is also the name of the injection given after delivery (more commonly known as `anti-D`).

PLEASE NOTE: A Rh(D) positive woman would never produce an antibody against a Rh(D) negative child, as positive blood does not produce `anti-d` - there is no anti-Rh(d).

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ANTIBODIES/ANTI-RH(D) AND THEIR EFFECTS

Antibodies against Rh(D) positive cells will be present in the mother`s bloodstream if she has previously had a Rh(D) positive baby and received no anti-D - in my experience most unlikely - midwives are just dying to stick a woman with an anti-D after delivery, appearing most disappointed when the baby is found to be negative and the mother is not in need of it! Antibodies will also be present if the mother has unknowingly had a placental bleed during pregnancy, causing fetal Rh(D) positive blood to mix with the mother's. If the mother has previously had a miscarriage or received a transfusion where Rh(D) positive blood was used, it is very likely that, if an adequate dose of anti-D was not administered at the time, her blood will contain Rh(D) antibodies.

PLEASE NOTE: A placental bleed (feto-maternal hemorrhage (FMH)) can occur during any pregnancy but, before we go any further, I would like to explain why it is much more unlikely for a woman to develop Rhesus (Rh) problems during her first:

The first time the Rhesus immune system encounters Rh(D) positive blood cells, it produces antibodies (IgM class antibodies) that are capable of destroying them. However, these antibodies are too large to travel through the blood vessel linking mother and baby`s blood and cannot harm the unborn child.  They are only effective in removing the positive cells from the mother's own bloodstream. It is the second and subsequent times such positive cells are encountered that the immune system will begin to produce a different type of antibody (class IgG antibodies) and, each time this occurs these antibodies react more `angrily` than the time before. Even though the `linking' blood vessel is only one cell wide, and not even the fetal and maternal bloods can mix this way, these new antibodies are of a shape and size that can easily pass through it, from the mother`s bloodstream to the baby. So, if a woman expecting her first child has a placental bleed during the pregnancy, she will produce the larger antibodies which can only destroy the positive cells circulating in her own blood. She would only start producing the more harmful antibodies if she suffered a further placental bleed. However, this is possible and the same care should be taken during a first pregnancy as with a second or subsequent pregnancy.

When Rh(D) positive cells find their way into a negative bloodstream for the first time, they remain `unnoticed` for about three days. After this time, the D antigen contained in these cells begins to stimulate the immune system into producing antibodies against them. When a woman`s own immune system has been stimulated into producing these antibodies, she is described as having been sensitized, which means that the first larger (IgM class) antibodies have been produced to destroy the positive red cells circulating in her own bloodstream. The immune system then `lays in wait` for the next shower of such cells to be encountered, ie. during a next pregnancy, so that the immediate production of the more harmful (IgG class) antibodies can begin. This is when the woman becomes Rh(D) Iso-immune - immunized against Rh(D) positive cells, even if they belong to her unborn child. Although the amount present may decrease over a period of time, these antibodies will remain in her bloodstream throughout her life, waiting to destroy any future invasion of Rh(D) positive red cells.

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THE PURPOSE OF ANTI-RH(D) INJECTIONS

After delivery, a blood test is performed to determine whether the baby is Rh(D) positive or negative. If the baby is tested Rh(D) positive, the mother will be given an injection of specially prepared anti-Rh(D), within three days (72 hours), in order to help her own blood destroy all the positive blood cells released into the bloodstream after the placenta comes away from the womb. This way, the blood cells are destroyed before the three days are up and her own immune system is not provoked into producing its own anti-Rh(D). Antibodies are only harmful if produced by the mother - the small amount injected after delivery is only there to do the job of `mopping up` the positive blood cells before they get to the immune system - they disappear from the bloodstream after a time.

100 micrograms of anti-Rh(D) will protect a woman from around 4ml of fetal blood. If the fetal-maternal hemorrhage (FMH) is more than 4 ml, a higher dosage is calculated and administered.

PLEASE NOTE: An anti-Rh(D) injection given at delivery is not a vaccine and does not make a woman immune to Rhesus (Rh) disease, but, provided she is found to be free of antibodies at the time it is administered, it can ensure that the woman begins the next pregnancy clear of antibodies.

Some Rh(D) negative women receive injections of anti-Rh(D) during pregnancy - especially at around 28 and/or 34 weeks - these would help to prevent antibodies being produced if an unsuspected placental bleed were to then occur, or had already occurred within the preceding 72 hours of the injection.

The amount injected is effective unless an unusually high amount of fetal blood enters the maternal bloodstream, thus `using up` the injected antibodies. In this respect, blood tests are still necessary throughout pregnancy to make sure that all is still well.

Each doctor follows guidelines set out by his/her own practice so a woman may find that she is not offered this treatment. However, administering anti-Rh(D) during pregnancy has been proved beneficial and it would be wise for a woman to discuss this with her doctor if she has any concerns about the welfare of her baby.

PLEASE NOTE: It is highly recommended that an anti-D injection be given after any incident which could result in red Rh(D) positive cells becoming present in the mother`s bloodstream, whether this be medical intervention where Rh(D) blood has been used, a fall which may cause a placental bleed, or a miscarriage.

ALSO NOTE: If a woman already has antibodies present in her blood a further administration of anti-D would be pointless and completely ineffective.

Although anti-Rh(D) is extremely effective, it is specially prepared using donor blood possessing high amounts of antibodies, the widespread use of this treatment has led to a number of women becoming immunized against red cell antigens unrelated to the Rhesus factor which, in rare circumstances, could also cause problems during a pregnancy, as well as there being a delay in providing blood for the mother herself in an emergency. However, the risks involved are outweighed enormously by the benefits of anti-Rh(D) and the injection should not be refused unless a woman is certain that her blood already contains Rh(D) antibodies.

If a Rh(D) negative woman is thought to be carrying a Rh(D) positive baby whose blood group differs from her own, you might ask why it is that her own in-built mechanism for destroying other blood types does not eliminate these cells from her bloodstream (Allo-immunization) before the D antigen contained in the Rh(D) positive cells stimulates her into producing Rh antibodies. While this would be so for some women, each person`s blood reacts in so many different ways, that it should never be assumed that the cells have been destroyed in time (within 72 hours). It is, therefore, standard procedure that every Rh(D) negative

woman has an anti-Rh(D) injection after delivery when the baby is found to be Rh(D) positive, whatever her blood group.

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IMPORTANCE OF BLOOD TESTS

At the beginning of a pregnancy, a woman`s blood is tested for the Rh(D) factor and, if she is found to be Rh(D) negative, further tests will be performed throughout the pregnancy to ensure that her blood is not producing Rh antibodies against her baby`s blood (see Antibodies and Their Effects).

If a bleed from the placenta should occur at any time during pregnancy and the fetal blood is Rh(D) positive, this would result in antibodies being produced. This is why it is essential to keep a note of when blood tests are due and what the results are. If results have not been received within a week after the test is performed, they should be `chased up`  - blood tests have been known to go astray. And, if a blood test is missed, it is vital that another one be arranged as soon as possible.

These tests are set out at carefully planned intervals throughout pregnancy to ensure that, if any antibodies are found in the bloodstream, the baby will not have been affected by them to such a degree that it would present a life threatening situation. Rhesus (Rh) disease (also called Hemolytic disease or Erythroblastosis Fetalis) takes weeks rather than days to affect the unborn child, so there would be ample time to check on the baby`s welfare and act accordingly.

It is written in pregnancy booklets that a Rh(D) negative woman should not be left to continue her pregnancy past her due date. The reason behind this is that, after the last carefully planned blood test, it is expected that the baby will be born on or before that date and, rather than perform another blood test, the baby will be delivered and any problems dealt with. It seems that this is not common practice.

In this respect, a woman who has not delivered by her due date should ask that a blood test be performed to put her mind at rest. While her doctor may insist that this is not necessary, babies suffering from Rh(D) disease have been known to die at full term and, even though this is a rare occurrence, this simple precaution should be taken.

PLEASE NOTE: If a baby`s blood is Rh(D) negative, it will not contain the D antigen and, therefore, cannot stimulate the mother`s immune system into producing antibodies throughout pregnancy or at labor and an anti-D is not necessary. Also, any antibodies already present in the mother`s blood cannot harm the baby`s negative cells. However, unless it is 100% certain that the partner is also Rh(D) negative, there will be no way of knowing the baby`s Rh factor during pregnancy and regular blood tests are still of utmost importance.

A recently developed test to determine the Rh factor of the baby by testing the amniotic fluid has been proving very effective. However, this test is only performed if a woman is already Rh(D) Rhesus iso-immune and her partner is known to possess both a positive and negative gene (d/D or D/d). This development is quite recent, but has proved very accurate and, although further blood tests will be performed regularly, a woman who is found to be carrying a Rh(D) negative baby will most probably be allowed to proceed with her pregnancy as normal.

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TREATMENT

Rh(D) antibodies attack the baby`s positive blood cells by coating and bursting them (hemolyzing), causing the baby to become slowly more and more anemic - a baby affected in this way would be described as having Rhesus ( Rh) disease (also called Hemolytic Disease of the Newborn (HDN), Hyperbilirubinemia or Erythroblastosis Fetalis). Each time a red blood cell is destroyed, a substance called bilirubin is released into the amniotic fluid, which causes these waters to become increasingly yellowed as more positive cells are destroyed.

The term `Rhesus disease` may lead you to believe that the condition is an illness which could affect the mother`s health. This is not true - her Rh antibodies cannot attack her own negative blood cells and will lie dormant in the bloodstream, and even decrease, until they encounter the next invasion of Rh(D) positive cells which would contain the D antigen capable of stimulating her into producing more. The only implications of the disease are those described on these pages and the only harm is to the unborn child.

If a blood test reveals that a dangerously high level of Rh(D) antibodies are present in the mother`s bloodstream, an amniocentesis will be performed - a sample of the amniotic fluid is taken and run through a machine which determines the level of bilirubin - the higher the degree of yellowing, the more the baby is affected. The results are compared carefully to a special chart (Liley chart), which shows whether the degree of yellowing proves the baby to be at risk.

These tests will be performed by a specialist, to whom the woman will have been quickly referred and who deals with Rhesus disease on a very regular basis. He/she will decide what action to take depending on the degree of anemia. The results may show that the baby is not so anemic, that action needs to be taken at that time. However, the woman would be asked to return every two weeks, or at intervals specified by the specialist, to retest the waters and keep a close check on how the anemia is progressing.

If, however, the results of the amniocentesis are plotted as high or higher than a line on the chart, called the Liley line, this would indicate that the baby is at risk and a transfusion into the umbilical cord will be performed under local anesthetic, whereby Rh(D) negative blood cells will be used to replace the positive ones destroyed. The amount of blood cells needed is cleverly determined by testing a sample of blood taken, by needle, from the cord (cordocentesis), guided using ultrasound. These results are quickly analyzed and the transfusion is performed there and then, using the already inserted needle, to minimize risk factors. This method is very successful and is sometimes repeated at intervals throughout the pregnancy, depending on subsequent test results. However, there may be occasions where the specialist is unable to insert the needle into the cord, or where the baby is in a position where the needle poses a risk and, in these circumstances, the needle will be inserted into the baby's abdominal cavity and injected slowly. Instead of being transfused directly into the baby's circulation, the blood will be absorbed over a small period of time. The mother would have been asked to arrive at the hospital an hour or so earlier than the transfusion is scheduled, in order that a sample of her blood can be taken and tested. This process is called cross-matching and enables the hospital's Hematology Department to find the closest match of donor Rh(D) negative blood. Not only does the donor blood have to be Rh(D) negative, it also has to be screened for any antigens, other than those related to the Rhesus Factor, which would stimulate the mother's immune system into destroying the newly transfused cells.

Although the mother's Rh antibodies cannot attack the transfused blood, the cells will diminish after a time and another test will be required two weeks later, again, to determine the amount of negative cells the baby needs to replace the positive ones destroyed. Even though the mother's antibody level is still checked at each stage of the treatment, it will most definitely rise to an extremely high level after the first and further transfusions.

It may be felt that it would be safer to deliver the baby and manage the baby's condition more directly, especially if the woman is more than 32 weeks into her pregnancy and the baby is at risk of developing severe Hemolytic Anemia. This is a very carefully made decision and one that depends on which situation

would give the baby a better chance of survival. As Pediatric medicine has progressed to a very high standard, it is usually considered much safer to do this.  However, if transfusions proceed until later in the pregnancy, say, 35 weeks, this increases the chance of a successful delivery nearer to full term and lessens the need for blood exchanges and other treatments.

If the baby is born early due to this condition, a transfusion is performed immediately to replace the baby`s blood with negative blood cells which remain in the system for about 40 days. About 9g of the baby`s blood is withdrawn and replaced at a time. Rh(D) negative cells are used to ensure that they cannot be harmed while helping the baby`s system to perform normally, which they do quite efficiently. They give the baby time to produce new positive cells, supplying enough blood to keep vital organs in good working order while this takes place. These Rh(D) negative cells will not harm the baby`s own newly produced cells, as there is no immune system to back them up. The blood used for this purpose is normally O Rh(D) negative and is cross-matched in the same way, to ensure that the transfused cells have no antigens to which the baby`s blood will take exception. Within as little as 72 hours the antibodies passed to the baby from the mother will have been eliminated.

If the anemia does not progress to the level that would require transfusions into the womb and a transfusion is not required at delivery, a special UV-ray lamp (Bililight) will be placed over the baby to combat any jaundice present (phototherapy). Close monitoring will ensure that the baby`s condition remains satisfactory.

PLEASE NOTE: Since the object of an anti-Rh(D) injection, is to prevent a woman from becoming sensitized and so becoming Rh(D) Iso-immune, the procedure would never benefit a woman with this condition. She will have plenty of anti-Rh(D) being manufactured by her own immune system and the injected antibodies would simply join forces with those already resident.

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ISO-IMMUNIZATION AND FUTURE PREGNANCY

As the Rh(D) antibody can cross the placenta from around 12 weeks, it is assumed that a baby would begin to become affected by the antibodies already present in the mother`s bloodstream from this time forward. For subsequent pregnancies a woman who is Rh(D) Iso-immune will have her blood tested at this time to check the level of antibodies present in her blood. This is measured in International Units (I/U). Obviously, it would be preferable to have no antibodies at all but, unfortunately, this would not be the case. However, if the level is measured to be less than 5 I/U, no action will be taken and further blood tests will be performed frequently to check this level. If the antibody level rises above 5 I/U, an amniocentesis is performed and, since it is possible that the baby may be Rh(D) negative, extra fluid will also be taken and tested at the same time to determine the Rh factor. This will also be the case if the mother is known to already have a higher level of antibodies than 5 I/U. An amniocentesis will be performed, along with a test to determine the baby's Rh factor, if necessary, along with an antibody check.

For reasons unknown, the woman`s antibody level still fluctuates slightly in response to a Rh(D) negative baby - not to such a high degree as during a Rh(D) positive pregnancy and, of course, no harm would come to a Rh(D) negative child.

Throughout the rest of the pregnancy, tests are done at intervals specified by the specialist taking care of that particular case. The length of time between testing depends on the degree by which the baby is affected, but can be as often as every two weeks. Also taken into consideration are the results of blood tests performed on the mother to determine the level of Rh(D) antibodies in her blood, which will rise as a Rh(D) positive pregnancy progresses and will be plotted on a Liley chart (see `Treatment`). It is usually at around 20 weeks, or later, that any intervention in respect of a transfusion is necessary.

Regarding transfusions and delivery, the same applies as when a placental bleed occurs during pregnancy (see `Treatment`), except that everybody is already totally aware of the situation and ready for action straight away.

PLEASE NOTE: When a woman is found to be carrying Rh(D) antibodies, the pregnancy is never allowed to go past full term. Once she has been diagnosed has being Rh(D) Iso-immune, and the specialists become involved, they take NO chances and, as they deal with this condition everyday, they have become experts in their field, with overwhelming success rates.

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NEW TREATMENTS - TRIALS

A new treatment, whereby the mother is transfused with non-specific (normal) human antibodies, is currently being used in trials.

If the mother's partner is known to be heterozygous (has both negative and positive genes), the baby's Rhesus factor is determined by either chorionic villus sampling (CVS) at around 11-12 weeks or amniocentesis at around 12-14 weeks.  CVS is performed by taking a small sample of cells from the placenta, outside the amniotic sac and analyzing it.  This method is often used early into the pregnancy, as an amniocentesis cannot always be performed at this time and the results of a CVS are available within a few days - the results of an amniocentesis take a little longer.  If the baby is found to be Rh(D) positive, the mother will immediately receive a transfusion of these normal antibodies on a daily basis for one week, after which the transfusions will be administered weekly until around 28 weeks.  These transfusions take around 2 hours and are stopped immediately if the mother develops any adverse reaction to the treatment, such as a rash etc.  So far, the only common side effect reported has been an occasional headache just after treatment, which has not caused any further problems for the mother. The normal antibodies help to protect the baby's red blood cells from the mother's harmful Rh(D) antibodies.

It has been considered that a safer option would be to begin treatment without CVS and perform an amniocentesis a few weeks later, to determine the Rh factor of the baby.  This would be a decision that needs to be made between the specialist and the patient.

NOTE:  If the mother's partner is known to be homozygous (having only Rh(D) positive genes), she will automatically go ahead with the transfusions, as there will be no need for CVS.

The same routine checks are still used to monitor the baby throughout the pregnancy - ie. amniocenteses and the mother's antibody check, as this treatment is still only being carried out in trials.

At present, this treatment is only offered to women whose condition has become so severe that their baby could be at risk.  The trials have so far been very successful, in that a transfusion into the womb becomes necessary much later in pregnancy, if at all, giving the baby a far greater chance of survival.

Unfortunately, even though this treatment has been very successful in severe cases, it has not yet been clinically proven as a definite advantage and is, therefore, very expensive and not widely available as a result.  Until a much larger number of women participating in these trials have delivered successfully, it will be a long time before any significant benefits are seen.

Another recent success had been seen in China, where a blood test is performed on the mother, to determine the baby's Rh factor.  The immature genes from the baby are detected in her blood and analyzed.  This test has been unreliable in the first trimester (up to around 13 weeks) but very accurate during the last two trimesters.  The test will not be widely available for a while, but it is a real step forward.

Treatment for Hemophilia / Haemophilia

Up to a few decades ago a considerable proportion of patients with hemophilia died prematurely because of hemophilia. Tragically, many deaths were the result of childhood injury or surgery. Over the last forty years treatment has advanced so much that the vast majority of patients today are expected to live long and active lives.

The main breakthrough in treatment occurred when coagulation factor deficiencies linked to hemophilia could be identified and then replaced, using products derived from human blood.

In the past patients used to receive whole blood or plasma infusions to control episodes of bleeding. Even though this helped, levels of clotting factors, especially factors VIII and IX, never reached the levels required for really effective blood coagulation, nor could these levels be sustained - in other words, serious bleeding was only partly treated.

Cryoprecipitate, made through the cold precipitation of frozen plasma from1965 onwards, was the first really effective treatment for hemophilia A. Freeze-dried concentrates made from human plasma containing the right levels of Factors VIII and IX became available in the late 1960s and early 1970s. Being able to keep the treatment at home and use it as required meant that patients could travel, leave the home, go to work, and enjoy a level of independence. However, a large number of patients subsequently became infected with blood-borne pathogens, such as hepatitis B, hepatitis C and HIV.

From the mid 1980s rigorous donor selection and viral inactivation procedures reduced the risk of blood-borne viral transmission to nearly zero. During the 1990s it became possible to prepare synthetic (recombinant) factors, using specially prepared mammalian cells and these recombinant concentrates are now widely used.

Hemophilia treatment will mainly depend on its severity and for patients with Hemophilia A or B involves clotting factor replacement therapy. There are two approaches:

• On demand - giving treatment to stop prolonged bleeding when it occurs. This is more common in the management of patients with mild hemophilia.
• Preventative treatment (prophylaxis) - medication to prevent bleeding episodes, and subsequent complications, such as joint and/or muscle damage. More commonly used for patients with moderate or severe hemophilia.

Clotting factor concentrates

Clotting factor concentrates can be made in two different ways:

• Plasma-derived clotting factors - prepared from the plasma of donated human blood.
• Recombinant clotting factors - the first generation of recombinant products use animal products in the culture medium and had human albumin (a human blood product) added as a stabiliser. Second generation products use animal-derived materials in the culture medium but do not have added albumin and instead use sucrose or other non-human derived material as a stabiliser. Third generation clotting factors have no albumin present at any stage of their preparation. Mouse monoclonal antibodies have been routinely used in the purification of coagulation factors for many years but a recently licensed recombinant factor VIII employs a synthetic ligand for this step. This has resulted in the production of the first factor VIII concentrate to be free of all exogenous human and animal protein, a goal which was reached for hemophilia B when the first recombinant factor IX was licensed in 1997.

Desmopressin (DDAVP)(for mild hemophilia A)

This medication is a synthetic hormone which encourages the body to produce more of its own Factor VIII. It is unsuitable for patients with hemophilia B and those with severe hemophilia A. In patients with milder forms of hemophilia A, factor VIII replacement therapy may be necessary, especially for severe bleeds, or after serious injury or major surgery.

RICE (Rest, Ice, Compression, Elevation)

RICE is a treatment many health care professionals recommend for joint bleeds. It also reduces swelling and tissue damage when used together with clotting factor concentrates.

Administering clotting factor concentrates

The medication is injected into a vein - generally in the back of the hand or at the crook of the elbow. Initial treatments are usually administered by a doctor or nurse at a hospital or clinic. Most adults can learn how to do this themselves, which means they can stop bleeding rapidly and effectively wherever they are.

If the patient is a child the parents or caregivers (UK/Ireland/Australia: carers) can learn how to administer treatment. The majority of very young patients can receive most of their treatment at home.

If a patient is finding it hard to access a suitable vein, or if intensive treatment is required, a port-a-cath, or an external catheter called a Broviac or Hickman line can be placed surgically into a vein, allowing factor replacement therapies to be given, and blood to be drawn easily for routine emergency tests. The use of such catheters can be complicated by infection and blockage and they have to be used with great care.

Treating bleeds

Bleeding episodes (bleeds) are an inevitable complication for patients with hemophilia A and B, even for patients with mild forms. As the underlying problem is one of prolonged bleeding, rather than rapid bleeding, they often appear not to be medical emergencies.
If a person with hemophilia experiences any of the following he should seek immediate skilled medical help:

• There is an injury to the neck, mouth, tongue, face or eye.
• There is a severe blow to the head.
• Bleeding is heavy or persistent.
• There is severe pain or swelling in any part of the body.
• An open wound requires stitching.

Most other bleeds, such as joint/muscle bleeds, small injuries and cuts that do not require stitches, and nosebleeds are generally treated at home, but patients should always seek the advice of a healthcare professional when in doubt. Any treatment will be more effective if it is started early.

Storing treatment

Factor concentrates should usually be stored in a refrigerator but are stable at room temperature for quite long periods. They should not be frozen as this may damage the vials or syringes. Some may be taken out for travel but should ideally be kept in a cool bag. Read instructions on product storage. If you are unsure, check with a health care professional or qualified pharmacist.

Inhibitors

Approximately 30% of people with severe hemophilia A develop antibodies to transfused factor VIII, usually shortly after their first few treatments. These antibodies (also called inhibitors) prevent the factor VIIII treatment working properly. It is often the case that, after a while, the inhibitors disappear and only about 10% or less of people with severe hemophilia A will suffer from long term inhibitors. In recent years it has become possible to prevent inhibitors becoming persistent through immune tolerance induction therapy. Where inhibitors do not respond to this approach alternative treatments are available.

Inhibitors rarely develop in mild hemophilia A or in hemophilia B of any severity.