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, 33 (5), 784-792

A Practical Blueprint to Systematically Study Life-Long Health Consequences of Novel Medically Assisted Reproductive Treatments


A Practical Blueprint to Systematically Study Life-Long Health Consequences of Novel Medically Assisted Reproductive Treatments

Callista L Mulder et al. Hum Reprod.


In medicine, safety and efficacy are the two pillars on which the implementation of novel treatments rest. To protect the patient from unnecessary or unsafe treatments, usually, a stringent path of (pre) clinical testing is followed before a treatment is introduced into routine patient care. However, in reproductive medicine several techniques have been clinically introduced without elaborate preclinical studies. Moreover, novel reproductive techniques may harbor safety risks not only for the patients undergoing treatment, but also for the offspring conceived through these techniques. If preclinical (animal) studies were performed, efficacy and functionality the upper hand. When a new medically assisted reproduction (MAR) treatment was proven effective (i.e. if it resulted in live birth) the treatment was often rapidly implemented in the clinic. For IVF, the first study on the long-term health of IVF children was published a decade after its clinical implementation. In more recent years, prospective follow-up studies have been conducted that provided the opportunity to study the health of large groups of children derived from different reproductive techniques. Although such studies have indicated differences between children conceived through MAR and children conceived naturally, results are often difficult to interpret due to the observational nature of these studies (and the associated risk of confounding factors, e.g. subfertility of the parents), differences in definitions of clinical outcome measures, lack of uniformity in assessment protocols and heterogeneity of the underlying reasons for fertility treatment. With more novel MARs waiting at the horizon, there is a need for a framework on how to assess safety of novel reproductive techniques in a preclinical (animal) setting before they are clinically implemented. In this article, we provide a blueprint for preclinical testing of safety and health of offspring generated by novel MARs using a mouse model involving an array of tests that comprise the entire lifespan. We urge scientists to perform the proposed extensive preclinical tests for novel reproductive techniques with the goal to acquire knowledge on efficacy and the possible health effects of to-be implemented reproductive techniques to safeguard quality of novel MARs.


Figure 1
Figure 1
Physiological tests in a timeline from birth to death in mouse versus human lifespan. The two life stages are child development and adulthood. Each stage includes examples of physiological tests with higher relevance according to the age period. The life cycle of a mouse is depicted in red and human in blue and the corresponding ages between the two species are presented below the illustrations for each stage. The extensive study of different developmental stages in mouse allows for the investigation of age-related developmental and metabolic disorders in human. (Images are adapted from Servier Medical Art by Servier ( and modified by the authors under the following terms: CREATIVE COMMONS Attribution 3.0 Unported (CC BY 3.0).)
Figure 2
Figure 2
Planning of neonatal tests in developing mice. Schematic representation of multiple morphological evaluations and reflex-ontogeny tests that can be performed in mice between 1 and 28 days of age. The dashed line corresponds to intermittent weight and length measurements while the full lines indicates continued analyses.

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