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Effects of an Alloimmunized Pregnancy

This page can be scary, but it’s important for you to know what may happen in your pregnancy and why having antibodies makes your pregnancy high-risk. We will walk you through an entire pregnancy listing all of the things that could happen. It is important to know that just because something could happen, it doesn’t mean that it will happen to you and your baby. Intrauterine transfusions (IUTs) are one of the things that scare women the most. Many, many women never need an IUT, but we still talk about them so that you are informed. We do not want you to be blind-sided if something does happen - we want to provide you with a resource to turn to for more information. This is the page to go to when you need to see everything and to know all of the options. We have included links to articles and other pages where you can go to get more information. You may want to print some of these pages off to discuss with your healthcare providers. 


What happens during pregnancy?

Your antibodies will cross the placenta. They may attach to the baby's red blood cells, and destroy them. This results in anemia and the production of bilirubin. Before birth the placenta filters out the bilirubin so there is no risk of high bilirubin during pregnancy. The largest problem during pregnancy is anemia. Currently the only universally accepted way to treat anemia is with a transfusion, but there are other options that may be considered experimental. These other options provide a few additional ways to attempt to reduce the risk of anemia or treat it. While many women never need the treatments below, these are options that may be offered to you or that you may wish to discuss with your healthcare provider.


Treatment Options During Pregnancy


Intrauterine Transfusion (IUT)

When you see the term IUT, it means an Intrauterine Transfusion. Currently this is the only universally accepted treatment for anemia in utero. This is a blood transfusion for the baby while they are still inside of you. An IUT is done to prevent the baby from dying. When the baby is anemic, they do not have enough red blood cells for their body to work properly. Just like how we would die if we lost too much blood, the baby is losing too much blood and needs a transfusion. Doctor's usually have great results with IUTs. About 75% of babies with hydrops survive, while more than 90% of babies without hydrops survive (19). IUTs are generally done between 18 and 35 weeks. Sometimes an IUT can be done as early as 16 weeks, but it is very difficult to do before 18 weeks. After 35 weeks, there is more risk with doing an IUT compared with delivery and a transfusion after birth. 

IUTs are done anytime the baby is anemic (not just for ISO). For most doctors, an IUT will be done any time a baby's MoM reaches 1.5 or higher. Some doctors also do them on a schedule since the baby will need more blood as it grows (which is approximately every 3 weeks). Many doctors use a formula to calculate how long the blood will last based on starting and ending counts. How often an IUT is done depends on each individual case and the doctor. Ask your doctor when he thinks an IUT will need to be performed, and how often.

IUTs are done in the hospital. Usually in a surgical suite. IUT procedures vary by doctor and hospital. In general, you can expect: sedation for you and baby (sometimes paralytic will be given to the baby to prevent injury), and pain medication and anesthesia to numb the area. The doctor will use ultrasound to guide the needle into the umbilical cord of the baby and to monitor his health. If the baby is under too much stress, the procedure will be stopped and further action (such as immediate delivery) may be taken. Once the needle is in, a sample of the baby's blood will be taken and the hemoglobin (or hematocrit) will be checked. This is called a cordocentesis or percutaneous umbilical cord blood sampling (PUBS for short), and tells the doctor how anemic the baby is and how much blood will be needed. Once the amount of blood is decided, the doctor gives that exact amount to the baby and takes a final hemoglobin reading to see how successful the transfusion was. The needle is removed and it is off to recovery to rest and wait for the medications to wear off.

The doctor will probably continue to monitor baby for a few hours before sending you home. Some doctors prefer an overnight stay, while others do not. Depending on the doctor, you may be asked to be on bed rest, or reduced activity for a day or two before resuming your normal routine. Since IUTs carry a risk of infection, some doctors choose to give antibiotics as a regular part of care after an IUT.

Normal hemoglobin increases from about 10 to 11 g/dL at 17 weeks, to about 14 to 15 g/dL at term. If baby's hemoglobin is 2 g/dL lower than normal, he is considered mildly anemic, 2-7 g/dL lower is considered moderately anemic, and anything 7 g/dL or more below normal is considered severely anemic.

IUTs suppress the bone marrow. This means that baby will not make as many red blood cells. In many ways this is good because there will not be baby's own blood to be attacked by the antibodies. Instead, it will be donor blood that will be safe from attack. Because the bone marrow is suppressed, ISO babies are at risk for late onset anemia. Additional tests after birth will be used to closely monitor baby.

Note: If your baby has had IUTs, the state required newborn blood screening may be off (it may be testing donor blood and not baby’s blood), and should be repeated at 1 year of age.

You can read more about this treatment option here: 

http://www.uptodate.com/contents/intrauterine-fetal-transfusion-of-red-blood-cells



IVIG with Plasmapheresis

IVIG stands for intravenous immunoglobulin. IVIG is not a replacement for an IUT, but it may delay the need for an IUT and get the baby to an age when an IUT is possible. It is an infusion of mostly IgG immunoglobulins that is made by extracting the immunoglobulins from the plasma of ~1,000 donors. IVIG is usually done between 12 and 20 weeks. It is also sometimes used after birth to treat high bilirubin. IVIG blocks some of the receptors in the placenta and makes it so that the antibodies cannot cross over to the baby. It also makes it so that you will produce less antibodies because your body sees IVIG as an antibody and decides that it doesn't need to make any more. It may also make the baby better able to tolerate the effects of the antibodies. 

IVIG is usually done once per week. IVIG is administered slowly through an IV, or possibly a port depending on how often you need to receive treatment. IVIG can be administered at the hospital, outpatient infusion center, or doctor’s office. It can cause side effects like headache, nausea, vomiting, fever and fatigue. Many women report getting multi-day headaches from the IVIG. Your doctor may be able to give you something for the pain. Some women have an allergic reaction to the IVIG. If this is the case, talk with your doctor about trying a different brand. Some women have no reaction when they switch brands. Some women receive an antihistamine and acetaminophen before a transfusion to mitigate effects.

Plasmapheresis is a procedure where the blood is removed from the mother, the blood cells are returned, and the antibody-rich plasma is removed. This can decrease the amount of antibodies in the blood and lower the antibody titer. Plasmapheresis is usually done with IVIG for maximum effectiveness.

You can read more about this option here:
https://www.sciencedirect.com/science/article/pii/S0002937818304940

https://onlinelibrary.wiley.com/doi/abs/10.1111/trf.12633

https://www.karger.com/Article/Abstract/111599

https://www.dovepress.com/a-case-of-d-alloimmunization-in-pregnancy-successfully-treated-solely--peer-reviewed-article-JBM 

http://www.healthline.com/health/plasmapheresis#Effects2 



Phenobarbital

Phenobarbital is a pill that you swallow (typically 3 times per day) for the last 10 days of pregnancy. It is used to mature a baby's liver and improves liver function. When blood cells break down, they turn into bilirubin, which is removed by the liver. Getting the liver to mature faster can help reduce the amount of bilirubin and reduce jaundice.

You can read more about this treatment option here: 



Steroids

Steroids do not treat anemia, but they may be given to you to help mature the baby’s lungs in case of early delivery. If you are having IUTs, they may be given before an IUT, and before birth. The important thing to remember is that steroids artificially lower the MoM score - they make the baby seem better when in fact he is still anemic. An IUT should never be delayed because of a decrease in MoM after steroid administration. 

You can read more about steroids and the effect on PSV and MoM scores here: 

https://www.ncbi.nlm.nih.gov/pubmed/15925046 

https://www.ncbi.nlm.nih.gov/pubmed/11146241 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029999/ 

https://www.ncbi.nlm.nih.gov/pubmed/10759269 

http://www.sciencedirect.com/science/article/pii/S1110569011001336 



Erythropoietin 

Erythropoietin is a hormone produced by the kidneys. It promotes the formation of red blood cells by the bone marrow. It can be made in a laboratory and used as a treatment for anemia. Erythropoietin is not commonly given to the mother for the treatment of alloimmunization. It is used in the few rare cases when women cannot be transfused with blood products. By injecting the mother, the drug will cross the placenta and work in the fetus to promote the creation of blood cells. Erythropoietin is also done to help prevent late onset anemia. Especially in IUT babies, the bone marrow is suppressed, causing low levels of erythropoietin, and red blood cells are not being made. Erythropoietin is given to decrease the need for a transfusion. It appears to be most effective after 24 weeks gestation. How often you would receive Erythropoietin varies by doctor. 


You can read more about this treatment option here: 

http://www.ncbi.nlm.nih.gov/pubmed/8355933

http://www.medicinenet.com/erythropoietin/article.htm



M281 aka Nipocalimab

There is currently a clinical trial going on for pregnant women with anti-D and anti-Kell antibodies. Many doctors do not know about this study, so if you think you are a candidate, please follow the link below to print the information and get it to your doctor ASAP. Trial sites are opening up all the time and they will pay for travel expenses and lodging. 

M281 is a monoclonal antibody that is also called  Nipocalimab. It is designed to prevent Hemolytic Disease of the Fetus and Newborn by reducing how many antibodies are in mom's system (lowering titers), and by blocking the antibodies from crossing the placenta. It is an IV infusion given every week. While the study is only for anti-D and anti-Kell, the two most aggressive antibodies, it should work for all antibodies once the trial is finished and the drug given final approval. 

M281 Trial Criteria

  • Anti-D antibodies with a titer of 1:32 or higher     - OR - anti-Kell antibodies with a titer of 1:4 or higher. 

  • Between 8 and 13 weeks gestation.

  • Previous pregnancy with problems occurring at or before 24 weeks including: 

  • Severe anemia at the time of IUT    - OR -

  • Hydrops fetalis with MoM over 1.5     - OR -  

  • Loss with placenta/pathology reports indicating severe HDFN.

If you do not meet the trial criteria, there is a second trial going on to assess the outcomes of alloimmunized pregnancies. No medication is given and you can join at any gestation. This trial is just keeping track of your results and how your pregnancy goes. To learn more about the comparison trial visit: https://clinicaltrials.gov/ct2/show/NCT03755128?term=m281&draw=2&rank=6


You can read more about the M281 treatment option here: 

https://clinicaltrials.gov/ct2/show/NCT03842189?cond=m281&rank=3

https://www.uth.edu/news/story.htm?id=2a52b16f-5f73-4fb7-bbd1-9bfb2aa967ff&fbclid=IwAR1SfU2g5luZvt-bNAeDo0Ah9lSWE2P9aTktAYLx8JHxegtEqwk-7TUK_D

https://www.empr.com/home/news/drugs-in-the-pipeline/nipocalimab-gets-fast-tracked-for-hemolytic-disease-of-the-fetus-and-newborn/


HDFN Problems After Birth

The risk to your baby doesn’t end at birth. The antibodies can continue to affect your child for 12 weeks or longer if you have had an IUT. Many of these problems will be detectable with the tests that you will request for baby (Link). As a convenience to you, we offer a printable package which includes a record of care where you can keep track of your child’s results and see the normal laboratory values (link).


Anemia

Anemia happens when red blood cells are destroyed. Infants born to mothers with antibodies have what is called hemolytic anemia. Hemolytic anemia is caused by red blood cell destruction. Hemolytic anemia cannot be treated with iron. Iron supplements must be avoided for babies with hemolytic anemia unless a ferritin test is given. Delayed onset anemia is when an infant who was not anemic at birth becomes anemic later. It can happen up to 12 weeks old. It is checked for with routine hemoglobin or CBC tests until ~12 weeks of age. Untreated anemia can be fatal. If anemia is a concern, a consult with a pediatric hematologist may help. 


You can read more about hemolytic anemia and delayed onset anemia here:
https://emedicine.medscape.com/article/201066
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828194/

https://medlineplus.gov/anemia.html

https://kidshealth.org/en/parents/anemia-hemolytic.html


Hyperbilirubinemia

Hyperbilirubinemia is a fancy word for high levels of bilirubin. Sometimes this is referred to as jaundice. Bilirubin is released when blood cells are destroyed. It builds up in the infant’s blood system and can cause problems. Bilirubin levels tend to peak around days 4-6 with ISO babies. You will need to watch out for rebounding jaundice. ISO babies tend to have a decrease in bilirubin when on lights, but rapidly increase when the lights are removed. This can occur up to 3-4 days after removal from lights, so keep checking the bilirubin levels even after treatment has ended. Infants with HDFN are at high or medium risk for bilirubin complications. High bilirubin levels as an infant can damage tooth enamel and hearing. Untreated hyperbilirubinemia can lead to brain damage, kernicterus, BIND, or even death.

You can read more about hyperbilirubinemia here:
https://pediatrics.aappublications.org/content/114/1/297

https://www.tandfonline.com/doi/abs/10.1080/jmf.16.3.163.166



Kernicterus

Kernicterus is a yellow staining of the brain as a result of high levels of bilirubin. Signs of Kernicterus include a high pitched cry, arched back, and an inconsolable infant. Kernicterus can be a sign of bilirubin induced brain damage (also called BIND). The yellow staining of the brain is not reversible although if high levels of bilirubin are caught early and promptly treated, the brain damage can be mitigated.


You can read more about Kernicterus at:

http://pick-k.org

http://emedicine.medscape.com/article/975276-followup#showall

http://www.childrensmercy.org/kernicterus/

https://www.sciencedirect.com/science/article/pii/S1744165X06000199



Neutropenia

Neutropenia is a reduced level of neutrophils, a specialized kind of white blood cell. Neutropenia is often detected on a CBC and is a common side effect of HDFN. Infants with neutropenia may not be able to fight infections and extra precautions will have to be taken to avoid anyone in the household getting sick. Neutropenic infants may need antibiotics or hospitalization in order to fight infections. If neutropenia is a concern, a consult with a pediatric hematologist may help. 


You can read more about neutropenia here:

https://www.nlm.nih.gov/medlineplus/ency/article/007230.htm

http://www.ncbi.nlm.nih.gov/pubmed/3718645
https://www.blutspendedienst-west.de/ueber_uns/zentren_einrichtungen/leukozytenimmunologie_eng/nin.php



Thrombocytopenia

Thrombocytopenia is defined as a platelet count of less than 150 x 109/L. This value is the same regardless of age. Thrombocytopenia is detected with a CBC and is a common side effect of HDFN due to maternal alloimmunization. Infants with thrombocytopenia may bruise or bleed more easily. If severe enough, platelet transfusion may be ordered. If thrombocytopenia is a concern, a consult with a pediatric hematologist may help. 


You can read more about thrombocytopenia here:
https://www.nlm.nih.gov/medlineplus/ency/article/000586.htm

http://learn.pediatrics.ubc.ca/body-systems/neonate/neonatal-thrombocytopenia/



Treatment Options After Birth

It can be very scary seeing your child hooked up to IVs and monitors. He or she may be in a little bilirubin bed and unable to be held whenever you wish. It is important to remember that many babies do not need all of these treatments. A large number of infants with HDFN never need a blood transfusion, but they may still need IVIG and phototherapy. Do not worry and think that all of these treatments are a must for you child; they are simply available treatment options. 


Transfusion

A transfusion of red blood cells involves inserting an IV into your baby and slowly giving them additional blood. It is a highly effective, immediate treatment for anemia. These are generally done later with iso babies and may be referred to as “top up transfusions”.This kind of transfusion will not remove the antibodies, but it will put in new blood that is antigen negative into the baby. If you have anti-Kell, then your baby needs Kell negative blood or your antibodies will just destroy that too. Think of it as topping off the baby so that they’ve got enough blood until the child can start making his own blood. The risks of a RBC transfusion are lower than with an exchange transfusion. 

You can read more about red blood cell transfusions here:
https://kidshealth.org/en/parents/transfusions.html
https://emedicine.medscape.com/article/201066-treatment
https://www.ucsfbenioffchildrens.org/pdf/manuals/F42_Hemol.pdf


Exchange Transfusion
Exchange transfusions are done as a treatment for dangerously high levels of bilirubin. An exchange transfusion will quickly and efficiently remove much of the bilirubin in the baby’s system. Quick treatment is essential for reducing the risk of permanent brain damage. Exchange transfusions carry more risk than a regular transfusion. In this transfusion, they remove all of the baby's blood and replace it with donor blood. This is usually done twice, in what's called a double volume exchange. Exchange transfusions do remove some of the antibodies and can be very helpful when treating HDN. A study has shown that exchange transfusion reduces the need for top up transfusions 8-fold. 


You can read more about exchange transfusions here:
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0038-1647096

https://www.healthline.com/health/exchange-transfusion

https://medlineplus.gov/ency/article/002923.htm

https://uichildrens.org/health-library/exchange-transfusion



Erythropoietin

Erythropoietin is a hormone produced by the kidneys. It promotes the formation of red blood cells by the bone marrow. It can be made in a laboratory and used as a treatment for anemia. Erythropoietin is regularly injected into the baby to promote the creation of blood cells. Erythropoietin is also done to help prevent late onset anemia. Especially in IUT babies, the bone marrow is suppressed, causing low levels of natural erythropoietin, and as a result the red blood cells are not being made. Erythropoietin is given to decrease the need for a transfusion.


You can read more about Erythropoietin here:
http://www.ncbi.nlm.nih.gov/pubmed/8726237

http://www.ncbi.nlm.nih.gov/pubmed/8355933

http://www.medicinenet.com/erythropoietin/article.htm



Phototherapy

Phototherapy is the treatment for high levels of bilirubin (hyperbilirubinemia). It involves the administration of blue light with a wavelength of approximately 450nm. Baby sits inside an incubator with blue lights over him. In some cases, a wrap around light blanket may be used. Phototherapy changes bilirubin into a water soluble form which is easier for the neonate to excrete, thus reducing the bilirubin level. Phototherapy lights are the most effective when left on for a period of time. What you do not want is baby on lights for 12 hours, off overnight, and then back on in the morning. You want to keep the lights on until the bilirubin is at a safe level and declining regularly. Remove them 1 light at a time, and test for rebounding bilirubin levels. If baby rebounds, expect to go back under lights. Once baby isn't rebounding, and bilirubin is decreasing on its own, you're usually good to go.


You can read more about phototherapy here:
https://pediatrics.aappublications.org/content/114/1/297

https://onlinelibrary.wiley.com/doi/full/10.1111/vox.12265

https://www.nejm.org/doi/full/10.1056/nejmct0708376



IVIG

IVIG is used as a treatment for high levels of bilirubin and anemia. It is an infusion of mostly IgG immunoglobulins that is made by extracting the immunoglobulins from the plasma of ~1,000 donors. IVIG is usually done when bilirubin levels are at or near the threshold for exchange transfusion or when levels are still rising despite phototherapy. 


You can read more about IVIG here: 

https://pediatrics.aappublications.org/content/114/1/297

http://www.aboutkidshealth.ca/En/HealthAZ/Drugs/Pages/Intravenous-Immunoglobulin-IVIG.aspx

https://europepmc.org/article/med/25125032

https://www.tandfonline.com/doi/abs/10.1080/jmf.16.3.163.166





Long Term Outcomes

There is good news - over 90% of the babies born to women with alloimmunization survive, and most of them do it with no long-term effects. However, while most of the babies have no ill-effects, they can still happen. Here are a couple of studies that talk about the long term neurological (brain) and cardiovascular (heart) outcomes.


In the LOTUS study by Lindenburg and Smits-Wintjens, 291 children who had had IUTs due to HDFN were tested between ages 2-17. Cerebral palsy was found in 6 children (2.1%), severe development delay was found in 9 (3.1%), and bilateral deafness in 3 children (1%). The overall rate of neurodevelopmental impairment was 4.8% or 14/291. The factor that was the most likely to result in neurological impairment was the development of severe hydrops. Preventing fetal hydrops is the strongest predictor for neurodevelopment.


You can read more at:
https://www.ncbi.nlm.nih.gov/pubmed/22030316

https://www.ncbi.nlm.nih.gov/pubmed/18387863



Long-term Cardiovascular Outcome following Fetal Anemia and Intrauterine Transfusion by Wallace, Dalziel, et al reports that cardiovascular development may be altered after exposure to fetal anemia and IUTs. These changes may persist into adulthood and possibly increase the risk of cardiovascular disease. Adults who received an IUT as a fetus were found to have “smaller left ventricular volumes, increased relative left ventricular wall thickness, and decreased myocardial perfusion at rest.” These adults also had “increased low frequency-to-high frequency ratio on assessment of heart rate variability and reduced high-density lipoprotein concentration”. Study limitations include: IUT babies were compared with siblings who were not exposed to antibodies. IUT children were born at earlier gestational ages which may account for some of the changes. 


You can read more at:
http://dx.doi.org/10.1136/archdischild-2016-310984

https://adc.bmj.com/cgi/rapidpdf/archdischild-2016-310984