QOTW – Do women with HAE suffer more during pregnancy if their unborn child also has HAE? Can C1INH pass through the placenta?

Dec 7, 2015

‘When an HAE mother is carrying a child with or without HAE does the child’s C1 inhibitor pass through the placenta into the mother’s body? I have one daughter with HAE, while carrying her I was very sick. I have 2 other daughters without HAE–during those pregnancies I had very few if any attacks. My sister had a similar experience– she did well during a pregnancy with her son who does not have HAE.

Dr. C: This is an interesting observation. Pregnancy can have a variable effect on HAE attack severity and frequency. Some studies report an increase in the second and third trimesters but there is discrepancy in the literature—patients can even improve during pregnancy. This may relate in part to the variability in sensitivity to estrogen and hormone fluctuation between patients. It does appear consistent that abdominal attacks are the dominant site if the severity increases. For anyone who has been pregnant it is easy to imagine why this could be the case–a bit of a ‘design flaw’.
Turning to our reader’s question there are two large studies with, of course, two different answers. Dr Martinez-Saguer of Germany found that there was no influence on the increased frequency of attacks during pregnancy (83% of patients) with respect to whether the fetus had HAE. She did observe that mothers carrying a child with HAE had C1 inhibitor levels during the pregnancy that were lower than mothers carrying non-affected children (mean 18.9% vs 29.3%). Dr Farkas in Hungary reported different results. Again the influence of pregnancy on severity of disease varied with 48% of women being worse during pregnancy, 33% improved and 19% no influence. Abdominal attacks were again the most common site. In Dr Farkas’s cohort there was a correlation with increased numbers of attacks in the third trimester and the fetus being affected by HAE. There is actually no data on transplacental transport of C1 inhibitor which would perhaps shed more light on this question. Dr Farkas’s results would however mirror the personal experience of our reader and her sister.
Marc, you have been interested in the topic of HAE and women, do you have any additional clarity for our reader?

Dr R: Pregnancy can certainly have an influence on the frequency and severity of HAE attacks. However, the effect is a little bit unpredictable as the largest studies in this area have shown mixed results: some women have worsening HAE symptoms during pregnancy, some improve, and some see no significant change. And while most women have the same clinical course with each subsequent pregnancy, some women have a significantly different course with each pregnancy, as pointed out by the details of the question here. Because of this unpredictability, researchers have investigated factors that might provide some clue to the course in individual women. Such predictors would clearly be helpful in clinical preparation and management. To answer the question posed here specifically – 2 studies have looked at the issue as to whether a baby with C1INH-deficiency influences the mother’s HAE symptoms during pregnancy. One study showed that this is the case – that a higher frequency of maternal attacks was observed, particularly during the last trimester, if the baby had C1INH deficiency. The other study showed that the mother’s C1INH functional levels were lower if the baby had C1INH-def, but did not show an increased frequency of maternal attacks. So again – and this is a recurring theme in HAE – there’s a great deal of variability and it’s tough to make any general conclusions about HAE symptoms in pregnancy. Due to the relatively large molecular size of C1INH protein, it’s very unlikely that it crosses the placenta, but the answer to that question of placental transport isn’t definitively known.

Dr C: Sounds like we are on the same page. Are there additional findings that may influence whether the pregnancy will result in a higher likelihood of enhanced severity?

Dr R: Other factors have shown some predictive value regarding HAE course during pregnancy: Early age of HAE symptom onset in the mother appears associated with more frequent and severe attacks during pregnancy. Interestingly, women who reported mechanical trauma as a strong trigger for HAE attacks also reported more frequent and severe attacks during the entire course of pregnancy. So these are associations in large studies that give us some predictive clues, but with so much variability in HAE, there are always individual exceptions to these tendencies.

Dr C: Yes, with the disparate outcomes of these studies we perhaps need to follow the lead taken with asthma research orchestrated with multisite studies with shared design to get more definitive answers.
Bruce, you have been unusually quiet here—I know you must have some opinions on pregnancy that you would like to share with our readers. Also I would be interested about your thoughts regarding the lower levels of C1 inhibitor found in one of the studies failing to translate into more severe disease—can you comment on what is known about the correlation between C1INH levels and swelling?

Dr Z: I’m afraid that I’ll need to remain pretty quiet. Basically, there’s almost nothing known about this, and the little that has been reported has already been discussed. The lack of correlation between C1INH levels and disease severity has been known for quite some time. This can be a bit confusing because it matters whether C1INH protein or functional levels are measured. One paper did report a positive inverse relationship between C1INH functional levels and HAE severity. Nevertheless, the manuscript showing no increase in attacks in women carrying affected fetuses despite lower C1INH levels measured functional levels. So it seems that there is no simple explanation.

Dr. C: Thank you Bruce and Marc—I think the last line sums it up—no simple explanation for our reader. One thing that we did not bring up in our discussion is that in each of the studies on pregnancy that C1INH was safely used for treatment—again we are fortunate to now have effective therapy in the US that can be recommended during what is the most vulnerable point in development. We look forward to hearing from you and our next ‘Question of the Week’.

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