Post-marketing surveillance

Pregnant and lactating women face unique concerns due to the potential risks to the developing baby, and the developing infant respectively. This highlights the importance of surveillance of medical products during pregnancy and breastfeeding.

In addition, there is often limited ability to identify risks that may impact health later in the child’s or adolescent’s development. Moreover, serious adverse events are rare and difficult to detect as they require data from large numbers of patients. Additionally, for the same product, serious adverse events might be different for pregnant and lactating women from those observed in the general population. Finally, a lack of knowledge and/or records on background rates of adverse pregnancy outcomes makes it difficult to assess the benefit–risk ratio of treatments in pregnancy and during the lactation period.

There is therefore an urgent need to invest efforts in robust registries to collect drug and vaccine safety data during pregnancy and, ideally, during at least the first two years of life.

Challenges for effective surveillance of maternal health and ways to mitigate them

Pregnancy surveillance registers are often inadequate, with limited data comparability. The diversity of terminology, definitions, methods used to assess outcomes, as well as the variability of data elements collected, may present challenges for the analysis of available data. In addition, it is often difficult to link over-time events in an infant to the mother’s exposure(s) to medication.

The Global Advisory Committee on Vaccine Safety has produced guidance and communicated statements on the safety of medicinal products and produces alerts to support countries’ surveillance systems. WHO encourages the use of harmonized tools, standards and methods to facilitate surveillance and proposes that existing pregnancy exposure registers be used and expanded to this end.

In terms of operationalization and governance, there are several challenges affecting the sustainability of health systems including loss of information, loss of time and resources due to multiplication of initiatives and tools, high turnover of trained personnel and the use of standalone projects. Improving collaboration among researchers, will help to increase the amount of available, usable data and avoid the duplication of efforts, thus saving time and resources. Innovative methods and tools to support countries, however, must be tailored to the needs of each country.

Guidance to strengthen safety surveillance for maternal and newborn health

Safety surveillance (pharmacovigilance) is critical to inform the safety of medication use in pregnancy and the breastfeeding period. Several standards exist to guide safety surveillance. For communicable diseases, the “WHO Recommended Surveillance Standards” is a guide to good practice and may help to harmonize surveillance activities.

During Covid-19, WHO published a safety surveillance manual for COVID-19 vaccines in pregnant and lactating women. The document discusses factors to consider when monitoring the safety of COVID-19 vaccines administered to pregnant and lactating women. It describes how national routine adverse events following immunization surveillance should be adapted to cater for these specific populations using both passive and active surveillance methods. Specific considerations and limitations of each method are provided as well as tools for implementation.

WHO’s “Overview: Vaccine preventable diseases surveillance standards” provides WHO-recommended standards for conducting surveillance for vaccine-preventable diseases. It is designed to help national regulatory authorities understand disease burden and epidemiology and inform vaccine policy and strategy. Standards for specific vaccine-preventable diseases are also included for concerning diseases that may be mitigated by maternal and newborn vaccines.

These documents can be used as a model for new preventive health products. In addition, WHO has produced templates of protocols for observational studies as well as for cohort event monitoring for safety signal detection that can be tailored to local objectives and strategies.

Harmonization tools and methods

Following a call from WHO for a global approach to monitor the safety of vaccines in pregnancy, the Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) was created in 2015. GAIA has developed 21 maternal and neonatal definitions that looked explicitly at safety outcomes, in addition to the definition of maternal immunization.

A WHO interdepartmental task force, representing 12 areas of work, produced a core data set called the WHO minimum maternal and newborn health data set (mMNHDS). This data set comprises 15 indicators, obtained by consensus, and is completed by the catalogue data set that includes indicators specific for each area of work. It is recommended that all indicators use WHO definitions, which are standardized and can be operationalized in settings with limited resources, ensuring comparability of the results obtained among studies.

WHO also developed an open-access toolkit for antiretroviral research in pregnancy with new materials and guidance to implement research and surveillance for new antiretrovirals for use during pregnancy and the breastfeeding period. It comprises several templates, protocols, data sets and other materials that may be used for clinical trials of pre-qualified health products (post-marketing safety surveillance).

Efficient maternal health surveillance should include efficient benefit–risk analysis leading to a proportionate regulatory decision to ensure safe, efficient, high-quality medicinal products for pregnant and lactating women. It should also determine background rates of maternal and newborn conditions that will inform the benefit–risk ratio of new medicinal and repurposed products. As the rates change, based on population and local epidemiology, the WHO published protocols may be adapted by setting and by condition.

Promote sustainability to support safety monitoring of medicinal products

The sustainability of surveillance systems may be a challenge in settings where there are funding restrictions and/or high rates of staff turnover. In collaboration with PATH, WHO mapped and assessed pregnancy exposure registries in settings with limited resources. An important number of these registries are still active and the majority of them monitor drugs. The pregnancy exposure registries mapped are observational studies and comprise a variety of approaches, each with their own strengths and limitations.

It is recommended to continue the use of existing pregnancy exposure registries and further expand them to take into account local products and public health burden.

Reporting

Reporting remains one of the challenges that hinders the data meta-analysis of safety information for medicinal products used during pregnancy and the breastfeeding period. The limited number and the low quality of reports impede signal detection for adverse reactions during pregnancy and the breastfeeding period. Addressing this challenge calls for sensitization among researchers to increase reporting and for training of reporters in order to limit missing data.

In addition, EudraVigilance (a system for managing and analysing information on suspected adverse reactions to medicines which have been authorized or are being studied in clinical trials in the European Economic Area) and Vigibase (a global medicines safety database focused on post-marketing safety data) have developed or upgraded algorithms to capture maternal status and enable efficient signal detection.

Although countries allowing patient reporting are limited, there are many countries that have run campaigns aimed at both women and their families to encourage them to report potential adverse events to health-care professionals.

Several studies have demonstrated that to enhance reporting culture and improve both the quantity and quality of reports, it is important to provide feedback to health-care professionals on both the strengths and the weaknesses of reports received. Studies have also shown that a lack of reporting is mainly due to the limited understanding of some reporters on how the data will be used, on the regulatory decisions that have been taken following reporting; and the benefits to women of childbearing age and their families.