Special Situations Reporting – Use of a medicinal product during pregnancy and breastfeeding

The majority of medicinal products or chemical substances administered to a pregnant woman could have effects on the foetus either before the placenta is fully developed or subsequently, if they can cross the placenta to at least some extent. Substances used for therapeutic purposes in the mother have the potential to reach the foetus with the consequential potential for harmful effects, depending on whether the rate and extent of drug transfer results in sufficient concentrations within the foetus.

Medicinal products may have a different impact at different stages of pregnancy. The spectrum of effects varies according to the period of exposure. For example, the exposure to a teratogenic agent during the period of organogenesis may induce major malformation, growth retardation or death, while exposure during the second or third trimester may induce growth retardation, renal insufficiency, neurological disorders, stillbirth, etc.

On the other hand, exposure to a teratogenic agent during the first two weeks of pregnancy (3rd and 4th gestational week) may lead either to the death or to a normal preembryo according to the “all or nothing rule”; at this period zygotes and blastocysts contain omnipotent stem cells without any differentiation, therefore, teratogenic agents may lead to seriously damaged preembryos, which will not survive, or to less seriously damaged preembryos, which will survive with complete regeneration. Hence it is always important to collect information on medicinal exposure during pregnancy.

Reports, where the embryo or fetus may have been exposed to medicinal products (either through maternal exposure or transmission of a medicinal product via semen following paternal exposure), should be followed-up in order to collect information on the outcome of the pregnancy and development of the child after birth. When an active substance or one of its metabolites has a long half-life, this should be taken into account when assessing the possibility of exposure of the embryo, if the medicinal product was taken before conception.

When pregnant women or healthcare professionals contact marketing authorization holders to request information on the teratogenicity of a medicinal product or experience of use during pregnancy, reasonable attempts should be made to obtain information on any possible medicinal product exposure to the embryo or fetus and to follow-up on the outcome of the pregnancy.

Reports of exposure to medicinal products during pregnancy should contain as many detailed elements as possible in order to assess the causal relationships between any reported adverse events and the exposure to the suspected medicinal product.

Individual cases with an abnormal outcome associated with a medicinal product following exposure during pregnancy are classified as serious reports and should be reported.

This especially refers to:

• reports of congenital anomalies or developmental delay, in the fetus or the child;
• reports of fetal death and spontaneous abortion; and
• reports of suspected adverse reactions in the neonate that are classified as serious.
• Reports of induced termination of pregnancy without information on congenital malformation, reports of pregnancy exposure without outcome data or reports which have a normal outcome should not be reported since there is no suspected adverse reaction. These reports should however be collected and discussed in the periodic safety update reports. However, in certain circumstances, reports of pregnancy exposure with no suspected reactions may need to be reported. This may be a condition of the marketing authorization or stipulated in the risk management plan. Examples include pregnancy exposure to medicinal products contraindicated in pregnancy, or medicinal products with a special need for surveillance because of a high teratogenic potential (e.g. thalidomide, isotretinoin).
• A signal of a possible teratogenic effect (e.g. a cluster of similar abnormal outcomes) should be notified immediately to the regulatory authority.

Breastfeeding

Suspected adverse reactions which occur in infants following exposure to a medicinal product from breast milk should be reported to the regulatory authorities.