Hereditary Hemorrhagic Telangiectasia (HHT) and Pregnancy
• At Sun Feb 17, 08:23:00 PM 2008, Seri said…
I read your answers to the patient who had a Du-positive blood type . I was 18 and gave blood and was informed I am O-positive (Du-positive). I was not sexually active and of course never pregnant and I am white. My Dad was O-positive and Mom was A-positive. How can that be? I have never had a blood transfusion, but my husband and daughter have HHT and both have required blood. Should I or we be concerned about transfusions?
• At Fri Feb 29, 06:49:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…
To Seri Feb 17: Given your parents' blood types, there is no reason you couldn't have the blood type you were born with. One (at least) of your Rh-positive parents is Du-positive, the other is likely to be heterozygous (a carrier of only one dose) for the Rh-D antigen, and you simply inherited the Du-variant of Rh and the chromosome from the other parent that was Rh-D-negative. The Du-variant is sometimes referred to as the 'weak' Rh-D antigen, but technically this still makes you Rh-positive. You only need only one dose of any Rh-D or -Du gene to have that expressed on your blood cells. Du-positive women cannot become sensitized to the D-antigen. Therefore, Du-positive women do NOT need Rh-immune globulin (Rhogam) during their pregnancies. If you get it inadvertantly, it would probably not cause any harm to the baby, but you just don't need it. Du is very common, but not exclusively found, in Black women.
As far as the HHT (hereditary hemorrhagic telangiectasia) in your daughter and husband is concerned, that does not put you or a baby you are carrying at any risk for needing blood transfusions. Your daughter got that only from your husband and not from you. It is inherited in an autosomal dominant pattern, i.e., it too requires only one dose of the bad gene to be expressed. However, your daughter needs to be concerned if and when she ever gets pregnant (but maybe we can cross that bridge when she comes to it!).
HHT is a condition that is actually caused by at least two different gene mutations and affects about 1 in 5000 individuals. A defect in the ‘endoglin’ gene is found in HHT type 1 (HHT1) and a defect in ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming growth factor (TGF)-? superfamily, causes HHT type 2 (HHT2). You will sometimes find HHT referred to in the medical literature as Osler-Weber-Rendu (OWR) after the doctors who first described it and suspected the hereditary nature of the disease. Clinical findings in individuals with HHT result from abnormalities in the development of some of their blood vessels.
Arteries carry the well oxygenated blood from the heart under high pressure through smaller and smaller vessels until the tiniest vessels (the capillaries) are reached and where most oxygen and nutrient is exchanged between the blood and the body tissues. The deoxygenated and nutrient-depleted blood then exits the capillaries into the veins that return the blood under much lower pressure to the heart. Individuals with HHT have a tendency to develop blood vessels that lack the capillaries (very small blood vessels) between their arteries and veins. This means that in HHT, arteries (with their thick muscular walls which are able to withstand the high pressures) are connected to veins that are only designed to tolerate relatively low pressures.
The site at which the artery and the vein are connected tends to weaken with time, eventually ‘balloons’ out (and remember, once a balloon gets past a certain point, it is easier and easier to distend), and can eventually rupture, resulting in bleeding. When these vascular abnormalities involve the small blood vessels in the skin or mucous membranes, we call these abnormalities ‘telangiectasias’ and if larger vessels are involved, we call these arteriovenous malformations (AVMs). Obviously, the abnormalities only involve a small percentage of an individual’s blood vessels, but the expression of the condition is highly variable between individuals, even within the same family.
The vascular malformations in individuals with HHT tend to occur more frequently in certain tissue areas although the reasons for this are unknown: the skin (especially face and hands), mucous membranes of the nose and mouth, lining of the stomach and intestines (GI tract), as well as the lungs, liver and brain. The larger (AVM) tend to occur more frequently in the internal organs and may be relatively asymptomatic for years before they expand and/or rupture. The diagnosis of HHT is considered definite if three or more of the following four criteria are present, or suspected if two of the following four criteria are present:
• Nosebleeds: spontaneous and recurrent
• Telangiectasias: multiple, at characteristic sites, including lips, oral cavity, fingers and nose
• Internal telangiectasias or AVM: lung, brain, GI, liver or spinal
• Family history: parent, sibling or child with HHT
As I mentioned above, I am more worried about our reader’s daughter when it comes time for her to consider pregnancy. I am not particularly worried about any children she might have with regard to pregnancy outcome (unless of course she had a complication related to her HHT). Because the mutations for HHT are inherited in an autosomal (non-sex chromosome) dominant fashion, they can equally affect both male and female offspring. However, while in the womb, it is quite unusual for babies with HHT to develop complications related to it. Arteriovenous malformations in fetuses have been detected, are quite rare, and can be quite devastating, but I do not believe these have been clearly correlated with HHT. Studies have shown expression of the genetic abnormality in fetal tissues (Abdalla, et al., Hum Mol Genet 2000;9:1227-37), but this is not associated with adverse pregnancy outcome for the baby as far as I am aware.
In contrast, the mother with HHT can be another story altogether. During pregnancy, the plasma volume normally expands 30-50% and to accommodate this, the cardiac output increases and the blood vessels must also relax, reducing peripheral vascular resistance. This involves some degree of ‘softening’ of the connective tissues in the blood vessel walls. One could easily see that this combination of events might lead to complications in the pregnant woman with HHT. Indeed, catastrophic events in pregnant women with HHT related to enlargement or rupture of AVMs in the lungs (e.g., intrapulmonary shunt deterioration and fatal pulmonary hemorrhage), brain (cerebrovascular accidents), and liver have all been described (Shovlin, et al., QJM 1995;88:879-87). However, if care is taken in the evaluation and management of young women with HHT, prior to and during pregnancy, risk for the mothers can be reduced (Schwebel, et al., Gynecol Obste Invest 2007;65:142-44).
There is one last concern I wish to mention regarding the woman with HHT who is considering pregnancy. If she has had bleeding problems that required transfusion, she is at risk for ‘isoimmunization’ to red blood cell antigens for which she was not crossed-matched prior to transfusion (this might involve Rh-antigens other than D and also non-Rh antigens). Depending on which antigens these are, her baby may be more or less at risk for hemolytic anemia and/or hyperbilirubinemia.
If a woman has HHT and is considering pregnancy, or is already pregnant, the HHT International Foundation can refer her to a clinic or center that specializes in the diagnosis, management and treatment of HHT, both here in the U.S. and around the world.
Thanks for writing. Bet you didn’t realize your questions were so GREAT!