Dr. Lidiia Zhytnik is a post-doc researcher at UMC Amsterdam, The Netherlands and a member of OIFE’s Medical Advisory Board. She has been part of a team who made a narrative review to systematize novel insights into OI genetics, reproductive options, family planning, decision-making and ethical issues. The team aimed to fill the existing gaps in literature on OI & reproduction and bring the latest updates in advances of reproductive approaches for families with risk of OI to health care professionals, researchers and the OI-patient community in order to restore reproductive confidence of people with OI.

Tell us about your experience with OI-work and what you are working on!

I joined OI-work in 2012 during my Master studies in The University of Tartu, Estonia. Afterwards I continued OI research in genetics, looking at genotype-phenotype correlations and clinical variability in OI families as a PhD student in the University of Tartu. Currently I am working as a post-doc researcher in Amsterdam UMC developing various therapeutic approaches for OI (gene therapy and pharmacological therapy).

Tell us about the project “Reproductive options”

During my time in The University of Tartu we had a very successful collaboration with Prof. Andres Salumets and Competence Centre of Health Technologies, which specialize on reproductive medicine and biology. His research group are pioneers in Estonia of preimplantation genetic testing (PGT) of various disorders including OI. Additionally, they were interested in developing of non-invasive prenatal testing (NIPT) for OI and other monogenic disorders. This is how the collaboration between an Estonian OI research team and the reproductive medical biologists started.

As we were looking closer at the topic of OI & reproduction it became clear, that literature regarding the latest reproductive techniques applicable for OI and associated ethical concerns was very limited. Both professionals and OI people are missing important information, which should help them to advice and make one of the most important decisions in life – family planning. The work was funded by three different grants to the University of Tartu, Estonian University of Life Sciences and Competence Centre on Health Technologies

What is the review about?

The review is an example of a multidisciplinary team effort, which appeared as a result of collaboration between experts in reproductive medicine, OI research and ethics. Our work systematized novel insights into OI genetics, reproductive options, family planning, decision-making and ethical issues. We aimed to fill the existing gaps in literature on OI & reproduction with our narrative review and bring the latest updates in advances of reproductive approaches for families with risk of OI to health care professionals, researchers and the OI-patient community in order to restore reproductive confidence of people with OI.

What was the purpose behind it?

As a rare hereditary disorder, OI is associated with numerous reproductive challenges, underlined with variable choice of reproductive options, decision-making and ethical concerns. During my interviews for the genotype-phenotype correlation study of OI families, I noticed that family planning, lack of clarity and confidence and sometimes poor experiences regarding this question is a burden. For the Quality of Life 4 OI conference in 2019, I was asked to give a talk about expectations and needs of OI people in the fields of basic research. Interviews with OI-people about important topics in research showed that the importance of family planning guidance was a big concern. OI-people need something more than “50% chance to pass on the mutation”, which is the same as flipping a coin. As a person with OI myself, I also spent quite some time exploring this topic and thinking about OI and reproduction.

What were your most interesting findings?

There is no one universal best reproductive option for all OI families. In the center of the decision should be the final outcome, which the person with OI set themselves, based on their desire, circumstances and abilities. Afterwards, different reproductive strategies should be carefully evaluated and a best approach for the case should be chosen together with professionals.

We have created a diagram of decision tree for families with (risk of) OI to give an overview of all options available for OI family planning. In this way we wanted to support OI families in decision-making. The diagram concludes all information and various scenarios in family planning. Based on type of OI and inheritance pattern, it leads you to chances of disease transmission to offspring, and shows approaches and techniques of modern reproductive medicine which can be used to ensure birth of kids not affected with OI.

What are the reproductive approaches suitable for prospective parents faced with a risk of OI?

First of all, ethical and supportive attitude of clinicians is crucially important for OI patients, as family planning is extremely sensitive. We should spend more attention on sharing information about reproductive options with patients. In collaboration with patient organizations, we should improve patient education so that autonomous decisions of people with OI would be fully informed.

Early family planning, pre-pregnancy OI genetic testing or pre-carrier screening will increase availability of various options of fertilization and prenatal testing. For fertilization a few options are available: natural conception, in vitro fertilization (IVF) with donor cells or embryo, or preimplantation genetic testing (PGT-M). All methods have advantages and risks, thus each method should be evaluated, with a special attention given to the wishes, interests, health needs and opportunities of the OI person.

The field of rapidly evolving non-invasive prenatal testing (NIPT) techniques should be constantly followed. Although detection of OI in unborn babies where the mother is affected with OI, is still studied (soon I expect it to be available), detection of de novo OI and OI in unborn babies with an affected father are ready to use options in many locations. Non-invasive testing options such as NIPT and ultrasound should prevail for prenatal diagnosis. Prospective parents’ decisions regarding invasive prenatal testing methods such as CVS, amniocentesis and cordocentesis, which carry risks for the pregnancy, need to be made autonomously, but with support.

What are the ethical aspects?

Reproduction for people with genetic disorders is a very sensitive topic. The biggest concern is autonomous decision making and its consequences. Very important OI-specific ethical issues are a correct prediction of OI severity (clinical type) and lethality based on the genetic mutation, which is currently impossible due to lack of genotype-phenotype correlations, and additional yet to be studied factors which cause clinical OI severity. There is definitely insufficient research on fertility in OI patients, soft tissues in OI pregnancy, lack of ethical studies related to anxiety and stigmatization around reproductive decisions in OI families.

Did you have patient involvement in the project?

We involved a representative from OIFE in reading and reviewing the article text, because we wanted it to be clear to the community. We also revised carefully a decision tree diagram with support from the patient community. Although some parts of the review are more complicated for general reader, we hope that the OI-community can also directly benefit and use this work. We would like to thank Ute Wallentin for her comments and suggestions, which improved our work.

There is a lot of confusion around OI and inheritance. Do you have a simple and pedagogic way to describe the different types/classifications of OI in not too many words?

First of all, there are two types of classifications. The clinical types (OI types 1-5) and genetic types (OI types I-XX+). These are two different classifications, and none of them are perfect. If we can simplify the model, clinical classification – is like a rainbow. We have 5 types, clearly different (like colors in rainbow we can clearly see), however there are also many border-line types. It’s the same with rainbow, it is sometimes hard to say were exactly one color changes to other. See the illustration on the previous page for more details!

Genetic classification is like an iceberg. The tiny tip of it are only two genes, both for collagen 1 (COL1A1, COL1A2). And ~85% of OI people are on this tip. As a rule it is dominant OI, in other words – one mutation is enough for OI. For those OI people from the tip of an “iceberg” it is 50% chance of passing OI to offspring.
The bottom huge part of an “iceberg” are various other recessive genes (now we know ~20 of these OI genes). In the bottom part there are only ~15% of patients. If you are among the “iceberg bottom”, it is usually recessive OI. For recessive OI two mutations altering the same gene are needed. Risk of OI transmission is 25% if both parents are carriers (have one copy of the mutation each). There are also some exceptions, like type 5 (clinical). This is always due to the IFITM5 gene, dominant mutation, so 50% chance.

Any messages for the readers of OIFE Magazine?

The most important is what you want. Based on your own desire, go for professional support and together with them build a strategy. Reach for information, educate yourself, understand the risks, learn what is acceptable for you and what is not. If some of the services are not available in your country, reach expertise centers in neighboring regions. Here are top 5 take home messages for the OI-community:

• ~85-90% of OI patients have a 50% risk of OI transmission to the offspring (dominant OI).
• More than half of OI-cases appear without previous OI-history in the family (sporadic/de novo).
• There are people who do not have OI, but have a high risk of OI transmission to offspring (carriers of recessive OI mutations, parental gonadal mosaicism).
• If a parent has dominant OI, a prenatal genetic testing (PGT-M) can help to have a non-OI baby.
• It is possible to perform testing (NIPT) of OI in an unborn via a pregnant mother’s blood sample.