NOICH Study - Patient Information

In addition to the information you received from your doctor, this brochure is handed to you to provide you with written information about the NOICH Study. You are pregnant and you are known to have antibodies in your blood that can pass the placenta and destroy the platelets of your baby. Low platelets may cause bleeding in the baby before or after birth. The standard treatment of this disease, Fetal and Neonatal Alloimmune Thrombocytopenia, is giving a dose of 1 gram of immunoglobulins per kg maternal bodyweight once a week. The aim of this NOICH (which stands for No IntraCranial Hemorrhage, or no bleeding in the brain) study is to find out if we can improve the standard treatment by lowering the dose to 0.5 gram per kg per week.

Introduction:
Before agreeing to participate in this CLINICAL RESEARCH STUDY, it is important that you read and understand the following explanation of purpose, procedures, benefits and risks of this study. It also describes your right to withdraw from the study at any time. No guarantees or assurances can be made as to the results of the study. You have been advised to come to our unit because a blood test revealed a problem. The problem is that your body is making a chemical in your blood that is crossing into the baby’s blood and possibly destroying the platelets in the baby’s blood. Platelets are little cells in the blood needed to prevent bleeding. If the baby has a low platelet count, spontaneous bleeding may occur. These chemicals are called “antibodies” and are formed by the pregnant woman’s immune system. Another term for platelets are thrombocytes. This problem is called “Fetal and Neonatal Alloimmune Thrombocytopenia” (FNAIT, also called NAITP). “Allo” means the antibodies are formed against cells from outside the woman’s body, in this disease cells from the baby.

Why did this happen to your pregnancy?
This problem happens because of an in itself normal reaction by your body’s self-defense system. During an earlier pregnancy, platelet cells from the baby entered your blood. Because the type of platelets of the baby was different from your own platelets, your body reacted by producing antibodies against them. The type of platelets of the baby were the same as its father’s platelets. The platelets of the baby, and the father, are of the most common type, carrying a specific marker (“antigen”) on the cell’s surface. This antigen in named Human Platelet Antigen (HPA). Your platelets are lacking this antigen, we call this “negative for the antigen”. This disease only happens in couples that do not have the same type of platelet-antigens, and only when the woman is HPA-negative. It cannot be prevented. It is not very common in pregnancy, but quite a lot of women with your problem are sent to our unit - you are not unique, or alone.

Is this problem serious?
It can be very mild – with only a small amount of breakup of baby’s platelets, but also it can be very serious. Unfortunately if we ignore the problem, it can sometimes result in severe bleeding and damage in the baby’s brain or in the baby’s death, in a small number of cases.

How do we figure out how bad the problem is?
Unfortunately, we do not have a reliable test to tell us whether or not your baby will suffer from a bleeding. We know that a woman who had a child with a low platelet count at birth due to FNAIT is at high risk to have the same problem in the next pregnancy. Most babies born with low platelets fortunately do not suffer from serious bleeding, but some do. Currently there is no other option than to give treatment to all pregnant women with platelet antibodies carrying a fetus that is positive for the HPA-antigen.

What is the medication used to protect the baby from the antibodies?
Since more than 15 years, we know that immunoglobulins (IG) can help to reduce the effects of antibodies against platelets. The standard treatment for pregnant women with HPA-antibodies at risk for a baby with low platelets is weekly 1 gram per kg bodyweight of IG given directly into the bloodstream (called intravenously, or IV). The drug is abbreviated as IVIG. This IVIG is made from blood donated by many donors, and carefully cleaned from all possibly dangerous components. The drug is considered safe for pregnant women, although we do not have sufficient good studies to absolutely prove this. As with all drugs in pregnancy, we always try to give as little as possible.
Recent studies have suggested that the dose of 1 gram per kg per week might be unnecessarily high. We expect that the same protection to the baby may be possible using half that dose.
The best time in gestation to start the IVIG is also no known. Bleeding in the baby's brain before birth is rare. In most cases in which bleeding did happen, this was between 30 and 35 weeks gestation. Therefore, in the study the European centers have decided to start at 28 weeks gestation. Some centers, mainly in the USA, are used to starting the IVIG already at 20 weeks. For the study, we leave it to your own doctor to decide when to start. The only goal of the study is to compare 0.5 with 1 gram.
The same approach is taken for decisions on whether or not to check the fetal platelet count before birth. Some doctors choose to do this, by taking a blood sample from the baby's cord. Other doctors choose not to do a fetal blood sample before birth, as this procedure has some risk. For the study, we leave it up to the doctor, together with the pregnant woman of course, to decide on performing a blood sample, and on when and how the delivery will take place.

What is the study?
We are investigating whether a weekly dose of 0.5 gram per kg is equally good at prevention of low platelet counts and bleeding as the standard dose of 1 gram. The only way to properly find out is to compare a group of women receiving the new dose with a group of women getting the standard treatment. If you join the study, we will look after you in our usual way, but we will either give you 1 gram or 0.5 gram IVIG per kg per week. Before starting the treatment, the computer in the central coordinating centre in Stockholm, Sweden will tell us in which group you are in. Assigning to one group or the other by the computer is done strictly by chance, also called randomly, to make sure that at the end of the study the two groups are similar apart form the dose of IVIG. When the study is over, we will have the required scientific evidence to know if we can switch to using the lower 0.5 gram of IVIG instead of 1 gram to treat women with FNAIT.

What does joining the study mean for you?
We ask you for one sample of blood to be taken each time just before starting the IVIG, at the time of placing the iv (so no extra puncture). Furthermore, we would like to have three tubes of blood after delivery. After cutting the cord, we want to drain the blood that is left in the placenta. From these bloodsamples, we will measure the amount of HPA-antibodies and immuno-globulins. Some of the blood will be stored for testing at a later stage, when more advanced techniques are available to try and understand why some babies suffer from bleeding while others do not. The blood will be stored using anonymous coding. Finally, we may in the future contact you to ask about the health of your baby in the long run.

The care for your pregnancy will not be changed for this study. Your doctor will explain to you all details about the check-ups, the time to start the IVIG treatment and when and how the delivery will take place.

Risks of the study:
There are risks to your baby from the antibody problem, and there are risks from the drug (IVIG). For the women receiving the standard treatment of 1 gram IVIG, there is the risk of receiving possibly too much of this drug. Although the drug is produced from donated blood, we do not have evidence for serious side-effects at this time. For the women receiving the lower dose of 0.5 gram, there is the risk of the drug not being effective enough. From other studies we believe however that 0.5 gram should be just as effective as 1 gram. Like all of our patients, we will carefully discuss all these issues with you.

What are the benefits of joining the study?
If we can show that a lower dose of IVIG is as good as the higher dose, we can treat pregnant women with your problem with less medication. Can I say no to the study? Absolutely. If you do not want to joint the study, we will look after you to the best of our abilities, in our standard fashion.
Also, you can choose to drop out of the study at any time you like. Your participation in this study is voluntary. You may refuse to participate or withdraw from the study at any time. This will not affect the attitude of the study doctor or others involved in your care, the quality of care you will receive in this clinic, or any benefits you are entitled to receive. Also, you should know that by signing this consent form, the participants do not waive their rights, nor are the investigators, or involved institutions released from their legal and professional responsibilities.

Contact persons:
If you have any questions about this study, contact Dr. Dick Oepkes at d.oepkes@lumc.nl, or the study coordinator in the clinic where you receive your care.