April in Review: Newsletter
Articles, webinars, and cool things.
Lil Lit Review:
I appreciate that the article very clearly states at the beginning: “Funding: This study was funded by Myriad Genetics Inc., Salt Lake City, UT, USA.” The study is retrospective - the researchers utilized Myriad’s cell-free DNA results, which include assessment of rare autosomal aneuploidies (trisomies other than T13, T18, and T21), and compared them to a database of health outcomes, the Komodo Healthcare Map. Inclusion criteria included “a fetal fraction of ≥ 0.03 and a degree of mosaicism between 0.15 and 1.10.” “Pregnancy outcomes were identified using diagnosis codes, procedure codes, and pharmacy fills,” so there is reliance on correct coding in the database to determine the outcome, as opposed to direct outcome measurements.
Not all individuals included in the analyses had providers who explicitly ordered the test to include rare autosomal aneuploidies (RAA). The researchers evaluated the difference in care provided to those whose providers ordered RAA assessment versus those who did not. Understandably, more evaluation was performed for those whose providers ordered the assessment. However, the reason the provider ordered the assessment is not elucidated, and it may be that these were already considered high-risk cases.
About 1 in 400 pregnancies screen positive for RAA. The most common rare aneuploidies were trisomies of chromosomes 7, 20, 16, and 8. Pregnancy complications included fetal growth restriction (FGR), gestational diabetes, and pre-eclampsia. Trisomy 7 was associated with higher rates of complications. RAA-positive pregnancies were less likely to result in a live birth and more likely to result in preterm birth or miscarriage than those that screened negative.
Importantly, this data references cell-free screening results, not confirmed fetal diagnoses. The hypothesis is that while fetuses may be impacted, these effects may predominantly be due to placental aneuploidy. Currently, RAAs are not routinely recommended for testing. However, I think the most salient point in this article is the potential to recognize a possible cause of miscarriage. Testing of products of conception is not yet routine, and having a possible explanation for patients undergoing this experience can make a world of difference for coping and future management. Positive predictive value (PPV) was not discussed in the article, as they did not have diagnostic testing results from the pregnancies. PPV is likely one of the major limiting factors for offering RAA assessment more widely.
What’s your reason for not ordering RAAs - or do you?
Newborn screening is the most implemented population genetic screening program. Its aim is to improve health outcomes, whereas carrier screening, likely the most widely used fertility test, is aimed at enhancing parental reproductive autonomy. These panels are often complementary to one another but designed independently. Each must consider “the strength of evidence for gene‐disease association, disease prevalence, technical limitations, cost, local healthcare availability, and infrastructure.”
The study authors compared two panels: the Australian national expanded reproductive carrier screening study (Mackenzie's Mission) and a genomic newborn screening study (BabyScreen+).
A continued conversation in the realm of carrier screening is manifesting carriers—the tool is not intended to provide any health implications or recommendations for the individuals undergoing the assessment, but for some conditions, it may come up. This is also the case for testing a child - parents may also be uncovered to have the same condition as their child, given variable expressivity for the condition.
The panels differ in two major ways. One is that the newborn screen included autosomal dominant conditions, whereas the carrier screening focused only on X-linked and autosomal recessive conditions. Second, the carrier screen included many more conditions, many of which do not have treatment options or have later onset in childhood.
The authors encourage more harmonized panels in the carrier screening and newborn screening realms. However, given the different aims of the tests, should they assess similar conditions? Enhancing reproductive autonomy may include the option to prevent conceiving a pregnancy with a genetic condition that doesn’t have a treatment. Testing a newborn for a condition that isn’t expected to onset until ten years later may not be helpful information for new parents.
The most important point from this article is that the newborn screen does not assess the same conditions as carrier screening panels, so one does not replace the other.
To rescue or not to rescue immature oocytes: prospects and challenges
There seems to be more talk surrounding in vitro maturation (IVM) of oocytes. This article very clearly defines what this process looks like and makes a clear distinction: the typically IVF method involves maturing egg cells in the ovaries with hormonal injections, whereas in IVM, maturation is done in the lab setting, so patients usually do not require such high doses of hormonal injections. I didn’t realize this was performed clinically, so wanted to share. The paper goes over maturing oocytes after unsuccessful maturation via typical IVF - this approach is still in the research realm.
Upcoming Webinars:
Revvity’s Roundtable on Newborn Screening: Tuesday May 13th at 10am EST.
ASRM’s Demystifying the accuracy of PGT-A platforms: using validation data to inform clinical IVF practice: May 15th 3pm EST
People doing cool things:
I love when complicated topics can be broken down easily - this newsletter site does just that on a number of omics topics including when a rare variant isn’t actually rare. Variant interpretation is fascinating.
Check out allmyhealth: they have patient handouts on gene therapy, nutritional guides for individuals with various genetic conditions, financial guides, and general information on various diagnoses.
Inside Reproductive Health has fantastic podcasts and information regarding the landscape of the fertility industry.
The Executive Order to Expanding Access to In Vitro Fertilization clearly states and recognizes the need to “provid[e] support, awareness, and access to affordable fertility treatments can help these families navigate their path to parenthood with hope and confidence.”
Resolve’s synopsis: White House Executive Order Update: What we know, what we don't know, and what's next
I’m always concerned with how much our environment is impacting our abilities to conceive and am hopeful there will be movement on this front as well as the executive office has stated goals in this area as well. There are many articles on this topic such as the impact and presence on oocyte quality and sperm.
Ownership of “genetic testing”
I recently spoke with a colleague and asked why they don’t use lab genetic counselors to review test results for them, especially if they don’t have the bandwidth to do so themselves, as opposed to their current practice of not offering the test at all. They replied, “We don’t want to give that up,” in reference to the patients and the test.
There was an underlying assumption that genetic counselors, particularly those working in a clinic, own the responsibility for genetic testing. I completely understand, as we’re taught that certain tasks are our “responsibility” and that we need to be the ones conducting the service. Yet, the reality is that the volume of genetic testing being performed outweighs the capacity of any one provider to review all the results.
The Genetics Access and Testing Empowerment Working Group is focusing on this reality with trying to find ways to educate “non-genetics” providers on these tests and topics. I like following their LinkedIn posts. :)
What’s New with Modern Reproduction:
Learning a ton from those who are graciously offering their time to help me understand the genetic testing and genetic counseling paradigm in IVF. What I’m hearing most about genetic counseling are concerns about liability and bias—liability for the clinic and bias from genetic counselors who work with labs. Let me know if you agree or disagree at genetics@modernreproduction.org.