Patient questions drive study of PI, fertility, and pregnancy

As awareness of primary immunodeficiency (PI) rises and people with PI live longer, fuller lives, more people than ever are entering their family-building years with a PI diagnosis—and lots of questions. That’s what motivated Drs. Jessica Galant-Swafford of National Jewish Health in Denver, Colo., and Xiao Peng of Montefiore Einstein in the Bronx, N.Y., to launch the MIRACLE Task Force. MIRACLE is short for Maternal Immunity, Reproduction, and Inborn Errors of Immunity Collaboration: A Joint Effort on Fertility, Pregnancy Outcomes and Therapeutic Safety.

“At the last few [Clinical Immunology Society] CIS conferences, people were definitely getting up there asking questions about how to manage patients with [for example] STAT 1 gain of function and other genetically-driven immune disorders during pregnancy. You see it on the listservs more and more too,” said Peng. “So I think it's just drawing attention to the fact that we're all taking care of patients who want to have kids but are on therapies for which we have little data on pregnancy impact. And, in general, we still know too little about the impact of their diseases on conception and pregnancy.”

“There's a certain amount of times as a provider you can say ‘we don't know’ [before] you start to say, ‘OK, let's dive in a little bit and try to know more,’” Galant-Swafford agreed.

Peng relayed that the questions she gets asked the most are about whether the medications her patients take are safe to be on during pregnancy. But even simple questions, such as whether a pregnant individual with PI needs earlier postpartum follow-up with their obstetrician-gynecologist (OB/GYN) remain open.

Most studies to date on fertility and pregnancy in PI have focused on females with antibody deficiencies. There are also a number of studies on familial Mediterranean fever (FMF). FMF has a high prevalence in Middle Eastern and Mediterranean countries and is the most common autoinflammatory PI. However, for most PIs, there is very little published information.

Peng explained, “A major goal [of MIRACLE] is not to be as selective as cohorts have been in the past and to make sure a greater diversity of immunobiology is represented by our data.”

The first phase of MIRACLE consists of a pair of surveys, one for patients and one for the rheumatologist, immunologist, hematologist, or geneticist who refers them to the study. The extensive patient survey covers a whole host of topics: patients’ fertility and pregnancy experiences, questions and concerns they have, care that they have or have not received, and outcomes for both mothers and babies.

Galant-Swafford has already started enrolling participants. As part of the study, in addition to the survey, participants can consent to an optional live virtual interview to allow for more free-form storytelling about their experiences

“When my first enrolled participant told me after filling out the survey that there was more she wanted to say, it was just telling about the importance of this topic in the lives of people with PI,” said Galant-Swafford.

On the provider side, she and Peng want to know how healthcare providers are approaching fertility and pregnancy when managing patients with PI. Their project will dovetail nicely with a survey CIS is conducting of its clinician members. The CIS group also plans to publish a summary report of current studies with proposed practice guidelines within the next year.

One issue the researchers suspect will pop up is lack of communication and knowledge gaps between providers. Ideally, a couple affected by PI who are considering having a child would have a team of healthcare providers communicating with each other: the provider who treats PI (typically an immunologist or rheumatologist), a medical geneticist, an obstetrician-gynecologist, and a prenatal geneticist. Maternal-fetal medicine (MFM) and reproductive endocrinology and infertility (REI) providers might also need to be involved. But, getting everyone on the same page and exchanging information is a tall order.

Peng explained, “This is probably one field where there happens to be a huge gap, unlike other genetic diseases, where there is recognition of a medical genetics to prenatal genetics connection. Because most geneticists don't directly manage patients with immune disease, there is not that auto-connection.”

The second phase of MIRACLE will pull information from patients’ electronic medical records to look for patterns and correlations in more objective clinical data including laboratory studies and genetic data, but most importantly fertility and pregnancy outcomes. This analysis will clarify whether some of the observations made for patients with FMF and autoimmune disorders apply to other PIs as well.

Ultimately, Peng and Galant-Swafford want to give providers a toehold on how to follow and monitor individuals with PI through their family-building journey. For the final phase of the study, they plan to develop an electronic medical record tool and consensus clinical guidelines based on the insights from the survey and patients’ clinical data. The hope is to develop something with a measurable positive impact both on fertility and pregnancy outcomes, as well as patients’ experiences.

“If we think about all the things that we don't know, we could be paralyzed by that,” said Galant-Swafford. “But we have to start somewhere. We just have to start.”

MIRACLE has three phases and will include five clinical sites: National Jewish Health and Montefiore Einstein, as well as Columbia University, University of Colorado, and Medical College of Wisconsin. The study is open to any adult, male or female, with PI or suspected of having PI, who is seeing a healthcare provider at one of the study sites. The researchers hope to document a wide range of PIs, especially those that involve inflammation and immune dysregulation. Studies of patients with systemic autoimmune conditions, as well as those with FMF, suggest that inflammation and immune dysregulation have a major impact on fertility and pregnancy. The question is whether that holds true for other PIs and if there are monitoring and management strategies that help counter the risks.

Looking for information on fertility and pregnancy in PI? Check out our new page!