Today is world patient safety day, highlighting safe maternal and newborn care. Women who are pregnant sometimes need medicines. Sometimes the reason is a headache, an allergy or a chronic illness. Sometimes health problems start or get worse in pregnancy, like diabetes, morning sickness or high blood pressure. But often there is not enough evidence to give the woman trustworthy information about how her particular medicine might affect the fetus. To bridge the knowledge gap, we are now calling women and their doctors to contribute data by reporting medicine use in pregnancy! 

The ConcePTION project will build a system where women will be able to report medicine use in pregnancy. With all that information about pregnancies and medicines we can learn about miscarriages, stillbirth and malformations, and how children develop. Every report counts! If you are pregnant, or used a medicine during your pregnancy, you can ask your doctor or midwife to report for you. If you want to know how to report a pregnancy, have a look at our webpage on pregnancy and breastfeeding.

By Josepine Fernow

Epithelial cells play an important role in the production of breast milk and transfer of different substances from mother to baby through milk. The ConcePTION project has developed a model to produce epithelial cell cultures from pigs that can help us study medicine safety in breastfeeding. This model is described in a recent paper in Animals, and part of an effort to develop knowledge for women who need to decide between medical treatments and breastfeeding.

New mothers sometimes need medical treatments, which often leads to difficult choices between her own health and breastfeeding her baby. To be able to offer information that women and their doctors can trust, we need to understand how chemical substances transfer from mother to newborn, or what we would call xenobiotic transfer.

The ConcePTION project is committed to using animals responsibly and in accordance with the 3R-principle, which means reducing the number of animals used for research, refining methods and replacing animals whenever it is possible. In vitro methods, including cell cultures, are now indispensable approaches to complement animal data. According to Chiara Bernardini, technical research at the Department of Veterinary Medical Sciences, University of Bologna, this new method allows us to produce primary cell cultures from the mammary glands of pigs used in food production, collecting tissue from slaughterhouses instead of using lab animals.

“The approach uses mammary epithelial cells from conventional pigs, or pMECs for short. These primary cell lines are part of a ConcePTION toolbox of non-clinical models that will help develop translational knowledge for women and health care professionals about medicine safety in breastfeeding”, says Dr Chiara Bernardini.

According to Chiara Bernardini, the novelty is in how these primary cell lines are produced. In technical terms, the team developed a new method to obtain primary pMECs through a technical innovation that combines enzymatic-mechanical tissue dissociation with multi step culture selection. The pMECs cellular lines show a specific epithelial phenotype, a clear attitude to create an epithelial barrier and express the main ABC and SLC drug transporters.

According to the authors, pMECs will serve as a valid tool to study the mammary epithelial barrier function in vitro. Using this approach will help reduce the number of animals needed to develop models for medicines safety in breastfeeding in the ConcePTION project.

The paper is published in a special issue of Animals on Current Contribution to the Research Based on Animal Tissue and Cellular Models:  Bernardini C, La Mantia D, Salaroli R, Zannoni A, Nauwelaerts N, Deferm N, Ventrella D, Bacci ML, Sarli G, Bouisset-Leonard M, Annaert P, Forni M. Development of a Pig Mammary Epithelial Cell Culture Model as a Non-Clinical Tool for Studying Epithelial Barrier—A Contribution from the IMI-ConcePTION Project. Animals, volume 11 (no 7) (2021)

By Josepine Fernow

Want to know more about the ConcePTION approach to study medicines in breastfeeding? Watch this clip!

Studies of medicines safety and breastfeeding often involve animals. Now IMI’s CONCEPTION project has a plan that could deliver better results while also using fewer animals.

Around 50 % of women who have just given birth need medication, yet we still lack information on which medicines can be safely taken while breastfeeding. This means that new mums who want to breastfeed but require medication for their own health often face a stark choice: breastfeed the baby and hold off on taking the medication, or take the medication and stop breastfeeding.

One of the aims of IMI’s CONCEPTION project is to deliver knowledge, tools and resources to plug this massive data gap so that breastfeeding women and their doctors can take an informed decision about whether or not it is safe to breastfeed while taking a given medication. As part of this effort, the project is collecting samples of milk from breastfeeding women who are using medicines. However, on its own, this is not enough, and so the project is investigating other ways of studying which medicines are likely to make it into breast milk.

Currently, three types of models are used to help answer this question. Firstly, there are in vitro models, which consist of cells in a dish or test tube. These allow scientists to assess how easily medicines are likely to make it into breast milk, and CONCEPTION is working to improve these models.

Secondly, there are computer based (‘in silico’) models which can also be used to predict the presence of a drug in breast milk. Here again, CONCEPTION is improving these models.

Finally, there are animal (in vivo) models, which are useful for analysing the mechanics of how a medicine makes it into the breast milk. CONCEPTION researchers recently published an extensive review of the pros and cons of different animals as models for research on breastfeeding.

So far, most research in animals has been carried out on rodents, as well as on animals like cows whose milk is drunk by humans. However, rodents and cows are very different from humans, meaning that results in these animals may not accurately predict what will happen in humans. Taking into account aspects such as similarity to humans, ethics and practical points such as the amount of milk produced, the team conclude that Göttingen Minipigs may be the most promising animal model for this research. Because they are bred for research purposes, Göttingen Minipigs are standardised and this means fewer animals are needed for experiments. From a practical and ethical standpoint, they are large enough for milk to be collected easily and without disturbing lactation or the growth of the piglets.

Ultimately, the CONCEPTION team believes that the best way of studying which medicines get into breast milk is to combine in vivo, in vitro and in silico models.

‘We believe it is even better to combine in vitro and in vivo data. This allows us to understand the mechanisms, and to learn how to apply data generated in cells to a living organism. At the same time this approach strongly reduces the number of animals needed,’ says Nina Nauwelarts of the KU Leuven Drug Delivery and Disposition Lab in a video made by the project. ‘The combination of different non clinical methods will enable us to predict medicine transfer into human breastmilk and subsequent infant exposure via breastfeeding. This information will allow physicians to give evidence based advice to women about the use of medicines during breastfeeding.’

How would combining approaches work in practice? ‘The approaches used are directly connected through a continuous flow of information,’ explains Alberto Elmi of the University of Bologna. ‘Moreover, both in vitro and in vivo data feed the mathematical approaches of the in silico platform, and this will further strengthen the other models. In addition, use of the human lactation data collected elsewhere in the project will allow us to validate the in silico, in vivo and in vitro platforms.’

CONCEPTION has incorporated the ‘3Rs’ (i.e. the reduction, refinement and replacement of animals in research) into its work from the very beginning. However, Dr Elmi highlights a 4^th ‘R’: ‘In the project, a pivotal point is represented by transparency in animal data communication and ethics within the consortium, and the constant dissemination of results not only to the scientific community but also to the public. One of the milestones on which we are resting our communication strategies for the use of animals for experimental purposes is the fourth R: Responsibility.’

By Catherine Brett

This text was originally published on the Innovative Medicines Initiative website.

Find out more

Read CONCEPTION’s news story ‘Developing a model for how medicines transfer to breast milk’

Watch CONCEPTION’s video on the models