Most Severe Hemophilia Cases Tied to Mothers With No Family History, Study Finds
Well over 70% of children with severe hemophilia born in a region of Italy in the last 20 years were to women without a family history of the disease, data from a registry analysis show.
“Our data highlight the importance of genetic counselling, especially in families with apparently sporadic haemophilia cases, in which low proportions of carriers are diagnosed among … relatives,” the researchers wrote, as it can affect a woman’s reproductive choices, including prenatal testing.
The study, “The effect of carriers’ reproductive choices and pregnancy history on sporadic severe haemophilia: A 20-year retrospective study through a regional registry,” was published in the journal Haemophilia.
Hemophilia A and B are both caused by mutations in genes found on the X chromosome: the F8 gene in the case of hemophilia A, and the F9 gene in hemophilia B.
Women have two copies of the X chromosome, meaning they may carry a hemophilia-causing mutation in one of their X chromosomes but not develop disease symptoms. These women are known as hemophilia “carriers,” and though they show no signs of the disease, they can still pass the disease-causing mutation to their biological children.
Inherited mutations are estimated to account for 70% of hemophilia cases. The remaining 30% are called sporadic, since they stem from spontaneous mutations that have not been inherited and occur in people with no family history of the disease.
However, researchers at hemophilia centers in the Emilia-Romagna Regional Network — which runs a web-based registry — witnessed an increase in sporadic cases of severe hemophilia in the last 20 years. “More than two thirds of persons with severe hemophilia are sporadic cases,” the wrote in a December 2020 assessment.
These scientists analyzed the regional registry’s data, focusing on women who were related to a severe hemophilia A or B patient and underwent genetic counseling at their center from January 2001 to December 2020.
Women were grouped in four main categories, according to their degree of kinship: mothers, daughters, second-degree relatives (sisters, grandmothers, and granddaughters), and other-degree relatives (cousins, aunts of all degree on the mother’s side).
Over these 20 years, 102 people were diagnosed with severe hemophilia A or B at the center. In parallel, genetic counseling was offered to 182 female relatives. Of them, 114 were carriers.
Female carrier status was more frequently associated with familial cases when compared with sporadic cases (77% vs. 57%).
Researchers then focused on women of childbearing age (total 140; ages 18–42) to understand how reproductive choices and pregnancy history might influence the likelihood of sporadic versus familial hemophilia.
Among these 140 women, 94 were identified as carriers. Of them, 37 were related to people with a family history of hemophilia and 57 were relatives of people with sporadic cases.
A total of 67 pregnancies were recorded among 45 sporadic carriers and 39 pregnancies (four voluntary terminations) from 21 familial carriers.
Among sporadic carriers, 32 women — 31 mothers and one-other degree relative — had a baby boy who inherited a disease-causing mutation. Twenty-one of them decided not to become pregnant again.
The other 11 either underwent prenatal diagnosis during the first trimester of pregnancy (four women) or simply continued with the pregnancy (seven women; nine pregnancies). None of these women decided to voluntarily end their pregnancy.
Four out of the 45 sporadic carriers were aware of their carrier status (two daughters and two sisters of affected males) at their first pregnancy, and two opted for a prenatal diagnosis. Nine women who became pregnant before knowing they were carriers chose to have no further pregnancies.
In total, 15 of these 45 women were aware of their carrier status, and six of them — or 40% — opted to undergo prenatal diagnosis during pregnancy. These diagnosis found five female fetuses, and one unaffected male fetus, the researchers reported.
Among the 21 women who were familial carriers, 19 were aware of their carrier status when they became pregnant. Nine of these 19 (47%) opted to undergo a prenatal diagnosis in 11 out of 15 pregnancies. The test revealed five affected baby boys, with pregnancies voluntarily terminated in three cases.
The other 10 familial carriers did not choose a prenatal diagnosis (53%) for any of their 22 pregnancies, including one that was voluntarily ended. Among 21 newborns, nine were affected boys.
Between these two groups of women, analysis showed that 77% of children with severe hemophilia were born to sporadic carriers.
Sporadic carrier mothers more often avoided further pregnancies after a first affected child (45%) compared with familial mothers, who were more likely to become pregnant and decline a prenatal test (60%).
This study suggests that “sporadic offspring account for more than 70% of severe hemophilia cases,” the researchers wrote.
“This increasing proportion is likely to reflect the influence in reproductive choices of awareness of carriers’ status, particularly in sporadic mothers, and of prenatal diagnosis options,” they wrote.
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