P.II.A.2.1. Availability and interpretation of data
Pregnant women are often excluded from clinical trials due to ethical concerns, at the time of marketing authorization, assessment of potential risks associated with the use of medicinal products in pregnancy usually relies on the extrapolation from non-clinical data and on knowledge of adverse embryo/foetal reactions of other products with similar pharmacological properties.
There are many examples where the mechanism of action of the medicine is related to the mechanism of teratogenicity or adverse embryo/foetal reaction, and hence pharmacological-toxicological class effects have been observed. Consequently, when assessing potential risks for an active substance, known adverse pregnancy outcomes for another substance of the same class of medicinal products should be carefully considered. However, evidence of absence of harm to the child for one substance cannot be extrapolated to other substances of the same class and be interpreted as indicating the absence of a potential risk for these other substances. Exposure through semen is another route of exposure to the embryo or foetus. Whether this carries a risk in clinical practice is unknown at present, but this should be considered for highly teratogenic substances that are transmitted into semen.
Like pregnant women, breastfeeding women are usually excluded from clinical trials; therefore, the estimation of risks for breastfed infants at the time of marketing authorization may be based on pharmacokinetic (PK) data, on data about the severity of potential adverse reactions to the medicine in the user population, or data from experience with other products with similar pharmacological properties.
P.II.A.2.2 Adverse events related to physiological changes of pregnancy.
Physiological changes during pregnancy may result in changes in level of medicine in plasma in the pregnant women, which may lead to dose-related adverse reactions or under-treatment, either of which could have negative consequences on the pregnancy outcome through their impact on maternal health.
Furthermore, for medicinal products with a narrow therapeutic window, adverse reactions, or fluctuations in plasma levels known to occur in the general patient population treated with this medicine may have added or specific relevance during pregnancy due to exacerbated effects associated with physiological changes of pregnancy. In practice, the availability of specific data on these phenomena is limited, and generating such data may be difficult when the terms of marketing authorization are such that the product information advises not to use the medicine during pregnancy.
P.II.A.2.3 Susceptible periods and adverse pregnancy outcomes
Susceptibility of adverse pregnancy outcomes from medicine exposure varies at different stages of embryonic and foetal development. The impact of in utero medicine exposure depends on the ability of a medicine to cross the placenta, dose and duration of such exposure as well as the gestational age at which the exposure occurs (taking into account a product's pharmacokinetics half-life). Clinically, gestational age is usually calculated from the last menstrual period, but more accurately established from ultrasound diagnostics. Possible negative consequences of exposure include early pregnancy loss, births defects (teratogenicity), foetotoxic effects, adverse events on the neonate and delayed adverse events on the developing child. The timing of exposure impact table:
Table 1: Description of the impact of timing of exposure and pregnancy outcomes ( see GVP – Chapter III – Product- or Population-Specific Considerations: Pregnant and breastfeeding women. www.ema.europa)
Potential pregnancy adverse outcome
Interference in the first two weeks after conception may result in early pregnancy loss.
Organogenesis occurs and can therefore be interfered with, resulting in major birth defects. However, each congenital abnormality has its specific critical period, e.g. 148 neural tube defects between the gestational days 29 and 42 (i.e. between days 15 and 28 post-conception);
16 to delivery
During the remainder of embryofoetal development, although structural anomalies may also occur, interference mostly causes minor anomalies, impacts on growth or results in transient or permanent functional defects such as neurodevelopmental disorders;
Late pregnancy or during delivery
There is the potential for irreversible or reversible physiological impacts on the neonate. These particularly include premature closure of the ductus arteriosus, acute renal insufficiency or withdrawal reactions
Interference through exposure to environmental agents, including medicines, may result in pregnancy loss or stillbirth
It needs to be recognized that if a major teratogen mostly results in spontaneous pregnancy loss or stillbirth, then only evaluating the frequency of birth defects would underestimate the teratogenic impact. In epidemiology, this phenomenon is referred to as 'competing endpoints. Further, if a product causes birth defects through interference with organogenesis, exposure to it may also have a developmental impact later in pregnancy and the perturbed development in utero may have developmental consequences for the child. Some adverse pregnancy outcomes only become apparent long after exposure has occurred, as the child develops, irrespective of when the exposure occurred. Adverse pregnancy outcomes can therefore not be evaluated in isolation, and this needs to be accounted for in any evaluation or study design.
Overall, birth defects that are visible at birth are relatively frequent at around ~3% of all live births; however, the frequency of each individual birth defect is considerably lower (and has been reported as ranging from 1 in 700 to 1 in 30 000 live births, or less). If a product is harmful in utero, it is unlikely to cause a detectable increase in the frequency of all birth defects. Instead, the frequency of some specific, but not all birth defects, may increase. Typically, in the population of pregnant women there are limited numbers of exposure to a medicine; therefore, there will be an even smaller number of adverse pregnancy outcomes (i.e. 'adverse events of special interest' for data collection and analysis). This has implications for the numbers of spontaneously reported adverse events and on cases identified through post-authorization surveillance methods, as numbers are expected to be small, making it difficult to identify an increase in cases of a rare adverse reactions. It also means 'birth defects' in general should not be studied as one single outcome.P.II.A.1.4 Adverse events in the child following exposure through breastfeeding.
P.II.A.2.4. Adverse events in the child following exposure through breastfeeding.
Some medicinal products are excreted in breast milk through breastfeeding, which may have an immediate adverse event on the child (e.g., sedation, irritation, gastrointestinal disturbances). This risk will be higher especially for medicines excreted in breastmilk with a long half-life, there will be a risk of accumulation in the infant if the ingested quantity is larger than the infant's capacity for metabolizing and excreting the medicine. The risk to the child can rely on several factors, whether the mother takes a single dose or a few doses, or is under chronic treatment with the medicine, and whether she took the medicine already during pregnancy or initiated treatment during breastfeeding. PK data of a product in breast milk can help inform the level of exposure from breastfeeding. PK data in a child after intake of a medicine with breast milk provides some information about the possible risk to a child, and when an adverse reaction is suspected in a breastfed infant, it may be valuable to obtain a blood sample from the child.