Pharmacovigilance in pregnancy

Pregnant women are largely excluded from clinical trials during drug development, unless the drug is specifically intended for use in pregnancy. Therefore often little is known about the risk of harm for pregnant women and their babies at the time of drug registration, and this makes it challenging for prescribers and patients alike to make decisions about whether to use a (possibly essential) medicine or not. Teratology is the science concerning the causes, mechanisms, and manifestation of developmental deviations, the latter which may be of either a structural or functional nature (Ujházy 2012). Teratogens are environmental agents, including medicines, but also infections (e.g. viruses such as zika) and chemicals or pollutants, that interfere with the normal development of an embryo or foetus. Every woman in every pregnancy has a 3-4% risk of having a child with a significant congenital abnormality/birth defect, of which about 10 % are related to drugs, chemicals, infections, known maternal illnesses or other exposures (https://www.entis-org.eu). Understanding how teratogens cause their effects is important as it helps in preventing congenital abnormalities. Similarly, understanding how the physiological changes in pregnancy impact a drug’s pharmacological action and its pharmacokinetics is important in order to, for instance, optimise dosing in this population.

The onus is on manufacturers to continue to explore potential harm from their drug in populations excluded from the clinical trials post-registration. For pregnant women, this may entail spontaneous reports, record-linkage studies, birth defect or pregnancy registries (observational cohort studies measuring association between exposure(s), intentional and accidental, and the pregnancy outcome), and targeted clinical studies (EMA 2005, Grzeskowiak 2012, Schaefer 2008, Kennedy 2004). Other than manufacturers, independent organisations working towards establishing the safe use of medicines in pregnancy have been established in many parts of the world (see links below). Aside from providing information for health professionals and the public about the known or unknown effects of maternal exposures to drugs and chemicals, they may also conduct studies to investigate the incidence of poor foetal outcomes and their association with such exposures. These include birth defects but also other negative outcomes such as prematurity, miscarriages, stillbirths and continued developmental or behavioural disorders in the child. In contributing their data to regional networks it is then possible to increase the likelihood of understanding the aetiology of these outcomes and thereafter how they may be better prevented.

There is, however, a general lack of post-marketing surveillance of medicines in low and middle income countries (LMICs). This prevents or delays establishing the safety profile of life-saving medicines for conditions prevalent in those regions that pregnant women are particularly vulnerable to and that themselves, may have a negative impact on birth outcomes, such as malaria. However, more work is being undertaken, whether for specific classes of medicines or more generally (Mehta 2012). Training and capacity building activities for LMICs that focus on specific problematic exposures in LMICs, under a new term "teratovigilance" are also being established.

Aside from continued empirical research into the effects of medicines on birth outcomes, there is a need for more methodological research in this area (i.e. how best to conduct studies to answer questions about potential associations). This is also very important for LMICs, where innovative cost-effective methods should be established, such as harnessing surveillance activities already in place (Mosha 2014). The use of low-cost neonatal assessment tools that may be standardised in facilities that do not have access to sophisticated technology is also important (MiP Intergrowth). However, in these regions there may be a relatively poorer infrastructure for maintaining institutional medical, prescription or dispensing records, and more unregulated access to medicines, and this has the potential to impact the accurate recording of medical and drug histories to accurately establish exposure data (Allen 2012).

Useful links

• See the US Food and Drug Association Pregnancy Registries’ webpages for links to specific US registries (https://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm251314.htm)
• The Global Health network:
  • https://globalmotherchildresearch.tghn.org/
  • https://pregnancycolab.tghn.org/
  • https://intergrowth21.tghn.org/
  • https://zikalliance.tghn.org/
  • https://rede.tghn.org/
  • https://zikaplan.tghn.org/
  • https://zikainfection.tghn.org/
  • Building capacity for teratovigilance in Africa
  • The Teratology Society (www.teratology.org)
  • European Network of Teratogen Information Services (ENTIS) (http://www.entis-org.com)
  • Organisation of Teratogen Information Services (OTIS) (https://mothertobaby.org)
  • The Motherisk Program (http://www.motherisk.org/)
  • EUROCAT (http://www.eurocat.ulster.ac.uk)
  • International Clearinghouse for Birth Defects Monitoring Systems (http://www.icbd.org)
  • WHO resources for surveillance of birth defects (http://www.who.int/topics/congenital_anomalies/en/)
  • March of Dimes (http://www.marchofdimes.org/)
  • The Antiretroviral Pregnancy Registry (http://www.apregistry.com/Default.aspx)

References

Allen EN, Gomes M, Yevoo L, Egesah O, Clerk C, Byamugisha J, Mbonye A, Were E, Mehta U, Atuyambe LM. Influences on participant reporting in the World Health Organisation drugs exposure pregnancy registry; a qualitative study. BMC Health Serv Res. 2014 Oct 31;14:525.

European Medicines Agency. Guideline on the exposure to medicinal products during pregnancy: need for post-authorisation data. EMEA/CHMP/313666/2005 http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500011303.pdf

Grzeskowiak LE, Gilbert AL, Morrison JL. Investigating outcomes associated with medication use during pregnancy: a review of methodological challenges and observational study designs. Reproductive Toxicology (Elmsford, NY). 2012;33(3):280-9.

Kennedy DL, Uhl K, Kweder SL. Pregnancy exposure registries. Drug Safety. 2004;27(4):215-28.

Mehta U, Clerk C, Allen E, Yore M, Sevene E, Singlovic J, Petzold M, Mangiaterra V, Elefant E, Sullivan FM, Holmes LB, Gomes M. Protocol for a drugs exposure pregnancy registry for implementation in resource-limited settings. BMC Pregnancy Childbirth. 2012 Sep 3;12:89

Mosha D, Mazuguni F, Mrema S, Abdulla S, Genton B. Medication exposure during pregnancy: a pilot pharmacovigilance system using health and demographic surveillance platform. BMC Pregnancy Childbirth. 2014 Sep 15;14:322.

Schaefer C, Ornoy A, Clementi M, Meister R, Weber-Schoendorfer C. Using observational cohort data for studying drug effects on pregnancy outcome--methodological considerations. Reproductive Toxicology (Elmsford, NY). 2008;26(1):36-41.

Ujházy E, Mach M, Navarová J, Brucknerová I, Dubovický M. Teratology – past, present and future. Interdisciplinary Toxicology. 2012;5(4):163-168.