Pregnancy in aHUS No Longer Unadvised, But Still High-risk, Expert Says

Pregnancy is no longer medically unadvised, or contraindicated, as it once was, for women with a history of atypical hemolytic uremic syndrome (aHUS).

But it is still considered high risk, an expert emphasized on a recent webinar hosted by ERKNet, the European Rare Kidney Disease Reference Network.

The webinar, “Pregnancy-related TMA,” featured Fadi Fakhouri, MD, PhD, the head of the nephrology department at Lausanne University Hospital, in Switzerland, and a professor in the university’s faculty of biology and medicine.

Fakhouri discussed the latest data on pregnancy associated with aHUS and other thrombotic microangiopathies (TMAs). He also stressed the concerns that both pregnant women and their healthcare providers should consider when a mother-to-be has a TMA.

TMAs are a group of rare disorders characterized by the destruction of red blood cells, low levels of platelets, and the formation of blood clots in small blood vessels. These conditions lead to organ damage, namely kidney failure, among patients.

aHUS, a type of TMA, is caused by the abnormal activation of the complement system, a set of more than 30 blood proteins that contribute to the body’s natural immune defenses. Notably, mutations in complement system genes are estimated to cause the disease in roughly 60% of patients.

Due to the several blood-related and immunologic changes occurring in the body during pregnancy, it is a “high-risk [period] for various forms of TMAs and TMA-like diseases,” Fakhouri said.

Moreover, it is well-established that the complement system is activated during pregnancy to help the fertilized egg attach to the woman’s uterus. This process needs to be tightly regulated, Fakhouri said.

The combination of a naturally high-risk period for TMA with complement activation increases the risk of aHUS, Fakhouri noted. In agreement, previous studies have estimated that about 10–20% of aHUS diagnoses are associated with pregnancy.

Pregnancy-associated aHUS mostly occurs postpartum and a high proportion (41%) of these women also carry complement mutations, several studies have shown. Those findings suggest that carrying a child may trigger aHUS in women more susceptible to complement system malfunction.

Regarding treatment, both aHUS and pregnancy-associated aHUS are known to respond well to therapies targeting the C5 protein of the complement system, Fakhouri said. Such therapies include Soliris (eculizumab) and Ultomiris (ravulizumab), both developed by Alexion. Notably, however, there is limited data on Ultomiris when it comes to being pregnant.

The nephrologist, who specializes in diseases and conditions that affect the kidneys, emphasized that Soliris treatment during pregnancy does not ensure that complications will not occur.

“You have to keep in mind that eculizumab during pregnancy is not a guarantee that the pregnancy will be uneventful,” Fakhouri said.

Higher doses or shorter interval dosing may be needed to effectively control aHUS during pregnancy.

However, before being able to initiate appropriate treatment for this potentially life-threatening disease, clinicians are faced with the challenge of rapidly and correctly diagnosing pregnancy-associated aHUS, Fakhouri noted.

Given that this condition shares many clinical features with other pregnancy-associated TMAs, and that there is no reliable diagnostic blood test, an aHUS diagnosis is usually confirmed only after all other causes of TMA have been excluded.

With this in mind, Fakhouri and other TMA experts created the International Working Group on Pregnancy-Related Thrombotic Microangiopathies. The team of experts developed some guidelines to help clinicians distinguish aHUS from other causes of pregnancy-associated TMA.

The group also created an algorithm for the treatment of TMA occurring during and shortly after pregnancy.

When a positive diagnosis of pregnancy-associated aHUS is confirmed, anti-C5 therapy should be initiated and maintained for six months or until the woman achieves kidney function stabilization, Fakhouri said.

However, in women with mutations in complement genes, treatment discontinuation may not be safe. Thus, treatment decisions need to be made on a case-by-case basis, he said.

He shared a list of relevant information, also set up by the working group, that can be used to counsel women with a history of aHUS who want to have a baby.

The first emphasizes that pregnancy is no longer contraindicated in this patient population, given both the existence of efficient treatments and the relatively low risk (about 25%) of disease relapse during or after pregnancy.

In addition, breastfeeding while taking Soliris is not contraindicated either, Fakhouri said.

However, pregnancy in these women is still considered high-risk, and they must be closely monitored by a multidisciplinary team from the first weeks of gestation to three months after delivery. Notably, aHUS relapse in these women occurs more frequently during pregnancy than after delivery.

The risk of an aHUS relapse in pregnant patients is difficult to predict. But the experts recommend that women be in a long-term period of disease remission and have stable kidney function before becoming pregnant. Once pregnant, patients typically can continue their anti-C5 treatment.

According to Fakhouri, preventive treatment with Soliris or Ultomiris is not recommended in this patient population since close monitoring and prompt treatment initiation upon aHUS relapse are both clinically possible and cost-effective.