POLICY • BRIEF
European Institute of Women’s Health
Safely use Medicine: Pregnancy & Lactation
There is a lack of information about the safe use of medication during pregnancy and lactation for both women and their healthcare professionals. The U.S. Centers of Disease Control and Prevention (CDC) provide some information. The CDC estimates that 9 in 10 women use some form of medication during pregnancy and about 7 out of 10 take at least one prescription medicine.1 In contrast, Europe lacks an official information and advice resource; the website of the European Medicines Agency is silent on this topic. However, many women need to take medication during pregnancy to manage their health condition, so “in some cases, avoiding or stopping medication use during pregnancy may be more harmful than taking a medication.”2 As more women postpone pregnancy the use of medicines during pregnancy is likely to increase.
The protection of mother and child is of paramount importance. Since the Thalidomide tragedy of the early 1960s when the teratogenic effect of a morning sickness medication resulted in birth defects and death in babies, teratogenicity testing in animals is a mandatory requirement before medicines can be authorised and prescribed. While animal studies are a good indicator of some side effects, they do not offer certainty on the safety in use and application. Moreover, women remain under represented in clinical studies, and generally pregnant women are excluded from clinical trials for safety reasons. Yet, in reality, many pregnant women must take medicines during pregnancy for pre existing chronic conditions such as asthma, diabetes, hypertension, and depression or for short term conditions such as infection, cold or toothache.
Robust evidence of how a medicine works in pregnant women and its appropriate dosage is lacking. Thus, paradoxically, the very reason that pregnant women are excluded from clinical trials, to protect them, results in a safety concern and lack of protection for both mother and child during pregnancy.
The Risk of Birth Defects
Teratogenicity, the risk of congenital anomaly, malformations at birth, is a major concern with regard to the safety of medicines during pregnancy. During the first trimester of pregnancy, often before pregnancy is confirmed, the foetus undergoes a period of organogenesis, the formation and differentiation of organs and organ systems during embryonic development. This period extends from approximately the end of the second week through the twelfth week of gestation in humans. During this time, the embryo undergoes rapid growth and as a result, is extremely vulnerable to environmental hazards or toxic substances.
Any interference with the sequential processes involved with organogenesis can cause an arrest in development and results in one or more congenital anomalies.4,5 Consequently, pregnant women should be careful about their medication use during this period. Late exposure may also cause neurodevelopmental effects, which is of increasing concern.
The Impact of Birth Defects
It is estimated that over 5 million women give birth each year in Europe; in 2010, about 140,000 foetuses and babies in the EU27 had a major birth defect. Birth defects7 are estimated to have accounted for 11% of the European neonatal deaths in 2008.
Why Action is Needed
Promoting healthy pregnancy and safe childbirth is a goal of all European healthcare systems. Therefore, it is surprising how little information is available about the use of medicines during pregnancy.
Birth defects, stillbirth, and death are a harrowing experience for both women and their families. Women and their physicians need comprehensive safety information to make informed decisions about medication use during pregnancy in order to prevent birth defects from happening in the first place.
The safe use of medication during pregnancy is an unmet medical and societal need. There is little information available to determine the risks to both mother and child. Instead, the package information leaflets that accompany medicines carry a general warning that the medicine has not been tested on pregnant women and women are advised to consult their doctors. Approximately 90% of medications currently have no information about their potential to cause birth defects.8,9
Europe lacks a robust and comprehensive regulatory and information system
This is urgently needed to address the need for safe medicine use during pregnancy. Most medicines have not been tested on pregnant women, unless these are specifically intended for use during pregnancy. In order to improve maternal health and the health of the future generation, reliable and up to date information should be available and easily accessible to women who plan to become or are already pregnant as well as health professionals who provde advice to them. When a medicine receives its marketing authorisation, information about reproductive toxicity is only available from animal studies. These are limited in their ability to predict human teratogenesis. As pregnant women are mostly excluded from clinical trials, the safety of many medicines has not been established at the time of approval for use in pregnancy. So most medicines prescribed to pregnant women are either counter indicated or used off label and rigorous, systematic pharmacovigilance reporting is lacking.
For some medicines, pregnancy registries have been established; however these are generally too small and do not have sufficient power to detect moderate medication related congenital anomaly risk.
EUROmediCAT: Recommendations for a Comprehensive Pharmacovigilance System
EUROmediCAT, a four-year FP7 project, aims to build a European system for reproductive safety evaluation in order to systematically and comprehensively identify possible adverse effects of medicines used in pregnancy, at the earliest stage post marketing, as well as to monitor and evaluate safety measures taken in Europe. The project utilises data from fourteen population based EUROCAT congenital anomaly registries and seven healthcare databases.
EUROmediCAT focused on four medication groups for chronic conditions for which women and clinicians need evidence to balance benefit and risks of different treatment choices: anti-epileptics, insulin analogues, anti asthmatics, and anti depressants. Importantly, EUROmediCAT highlighted the need and importance for pre conception care.10,11
The findings of EUROmediCAT and its recommendations inform current regulatory practice, pharmacovigilance, research, and health policy and practice in order to do the following:
• Improve future pharmacovigilance
• Inform future drug safety measures
• Raise the level of reproductive pharmacovigilance to meet women’s expectations
Key EUROmediCAT Recommendations 12,13
1. The scarcity of information on medication safety in pregnancy, in relation to risks of congenital anomaly, neurobehavioural and other effects, is unacceptable. It must be remedied by more investment in research and pharmacovigilance. A mechanism whereby pharmaceutical companies contribute to an independent pharmacovigilance and research funding pot with ring fenced use for pregnancy and lactation is now an urgent need. This would both monitor new medicines and remedy the deficit of information on medicines currently and commonly used.
2. All new medicines to the market should be accompanied by specific monitoring of their effects on the foetus, infants, and women when prescribed during pregnancy and lactation. Regulatory powers must include revoking of licences should their information be insufficient in quantity, quality or timeliness and take into account the frequency and characteristics of their prescribing or use. (see EUROmediCAT recommendations 14,15)
The New EU Clinical Trials Regulation: A Major Step Forward in Patient Safety
The new EU Clinical Trial Regulation (No 536/2014) aims to create an environment that is favourable to conducting clinical trials in the EU with the highest standards of ethical and safety protection for participants.16 It contains new rules for the inclusions of pregnant and breastfeeding women in clinical studies under strict protective measures.
The Regulation, which becomes law in 2016, sets out the legal provisions under which clinical trials will have to be conducted in Europe in the future. Article 33, Chapter V defines the conditions for including pregnant and/or breastfeeding women in clinical trials, provided the protective measures outlined in the legislation are followed.17 As most pregnant women will still be excluded from clinical trials, there is an urgent need to conduct effective and rapid post-marketing studies for pregnant women and other vulnerable populations who otherwise would be excluded from clinical trials.
International Initiatives – The New FDA Rules on Pregnancy and Lactation
In 2014, the U.S. Food and Drug Administration (FDA) published new legislation that sets consistent standards for how information about using medicines during pregnancy and breast feeding through the labelling of prescription drugs and biological products.
Based on available information, the new labelling rule explains the potential benefits and risks for mother, foetus, and breastfeeding child. There are three subsections: “Pregnancy,” “Lactation” and “Females and Males of Reproductive Potential.” The information is intended to help healthcare professionals make prescribing and counselling decisions.
The Pregnancy subsection provides information relevant to the use of the drug in pregnant women, such as dosing and potential risks to the developing foetus, and requires information about whether or not there is a registry that collects and maintains data on how pregnant women are affected when they use the drug or biological product.
The Lactation subsection provides information about using the drug while breastfeeding, such as the amount of the drug in breast milk and any potential effects on the breastfed child.
The Females and Males of Reproductive Potential subsection includes information about pregnancy testing, contraception, and about infertility as it relates to the drug.18
The EUGenMed Research Project
The EUGenMed, an EU FP7 funded project, examined the sex and gender differences in biomedical and public health research. Within the project, the Workshop on Medicines Regulation highlighted the current information gap about women, including with regard to medicine use during pregnancy. The Workshop recommended that a robust regulatory and pharmacovigilance framework should be developed for safe use of medicines during pregnancy, which should include a comprehensive system for post-marketing data collection.20,21
Where Can Reliable Advice on Drug Safety During Pregnancy be Found?
Some women must take medication for pre-existing chronic diseases, such as asthma, diabetes, high blood pressure, HIV/AIDS, etc. Often the question of treating a chronic condition during pregnancy can cause anxiety and fear in the pregnant woman. Yet if these conditions are left untreated, both mother and unborn child can be in danger. In some cases, the risk of disease may be more severe than risk of treatment; therefore, better information must be collected and the results made urgently available to inform practice.
Websites, such as the U.S. Center for Disease Control and Prevention, advise that pregnant women should not stop or start taking any type of medication without first consulting their doctor.
Some countries in Europe, such as the UK and Germany, have teratogen information systems online. Ideally, women who are planning to become pregnant should discuss their medicinal needs with their doctor before becoming pregnant.
Increasingly pregnant women search for information on the Internet. It can be a dangerous if women buy teratogenic medications online. On the other hand, the Internet can also provide an opportunity to obtain information about medicine safety during pregnancy. The EUROmediCAT project examined this area and made the recommendation that the growing role of the Internet needs further evaluation to develop appropriate medication safety measures.
Preconception Information and Counselling of Women
Prevention across the lifespan is an important public health strategy. However, few prevention programmes include preconception health. As a better understanding of how the preconception environment can affect the health of the unborn child is gained, more efforts must be made to invest in prevention already at the preconception stage. The EIWH has highlighted various issues related to pregnancy, such as the danger of smoking, alcohol consumption as well as chronic diseases, including gestational diabetes. The current obesity epidemic also requires urgent action to prevent the risk of transgenerational transmission of diabetes during pregnancy.
The European Board and College of Obstetrics and Gyneacology (EBCOG) recommends that young women talk to their doctor preferably before stopping their anti conception measures. This provides an important opportunity to discuss healthy lifestyles by stopping smoking and vaping, reducing alcohol consumption, having a healthy diet to achieve a normal BMI before getting pregnant), update the vaccination status, start folic acid to reduce the risk of spina bifida, and to discuss preventive measures to avoid fetotoxic infections in pregnancy such as toxoplasmosis, cytomegalovirus (CMV) or hepatitis B.
Preconception also provides a time to motivate young women and future mothers to do the best for their baby. It is an opportunity for doctors and patients to go through past medical histories and check what medicines or supplements have been taken, etc.22
We wish to thank our expert reviewers:
Helen Dolk: Professor of Epidemiology and Health Services Research, Ulster University and Co-ordinator of EUROmediCAT
Andre van Assche: Em Professor OB/GYN Univ of Leuven, MD, PhD, FRCOG, Past president of EBCOG and member of the Executive Committee of EBCOG
Contributors: Hildrun Sundseth, Peggy Maguire, Kristin Semancik and Lisa Keenan December 2017
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10. EUROmediCAT, n.d., EUROmediCAT: Safety of Medication Use During Pregnancy, Available at: http://www.euromedicat.eu/content/EUROmediCAT-Leaflet.pdf.
11. EUROmediCAT, 2011, What is EUROmediCAT? Available at: http://www.euromedicat.eu/whatiseuromedicat.
12. 2015, “EUROmediCAT: Safety of Medication Use in Pregnancy,” Pharmacoepidemiol Drug Saf, 24, 3–7. doi: 10.1002/pds.3866.
SAFE USE OF MEDICINE DURING PREGNANCY 5
13. Dolk H, de Jong van den Berg L, Pierini A et al., 2015, “EUROmediCAT Recommendations: European Pharmacovigilance concerning Safety of Medication Use in Pregnancy,” Pharmacoepidemiology and Drug Safety, 24: 3-7, http://onlinelibrary.wiley.com/doi/10.1002/pds.3866/abstract.
14. 2015, “EUROmediCAT: Safety of Medication Use in Pregnancy,” Pharmacoepidemiol Drug Saf, 24, 3–7. doi: 10.1002/pds.3866.
15. Dolk H, de Jong van den Berg L, Pierini A et al., 2015, “EUROmediCAT Recommendations: European Pharmacovigilance concerning Safety of Medication Use in Pregnancy,” Pharmacoepidemiology and Drug Safety, 24: 3-7, http://onlinelibrary.wiley.com/doi/10.1002/pds.3866/abstract.
16. EUR-Lex, 2014, Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance, http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2014.158.01.0001.01.ENG.
17. EUR-Lex, 2014, Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance, http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2014.158.01.0001.01.ENG.
18. U.S. Food and Drug Administration, 2014, Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling, https:// www.federalregister.gov/articles/2014/12/04/2014-28241/content-and-format-of-labeling-for-human-prescription-drug-and-biological-products-requirements-for.
19. Telegraph, 2012, “Boosting breastfeeding rates saves lives and money.” http://www.telegraph.co.uk/health/healthnews/9614658/Boosting-breastfeeding-rates-saves-lives-and-moneyUnicef.html.
20. European Gender Medicine Project (EUGenMed), 2015, Workshop 4: “Sex and Gender in Medicines Regulation and Medical Education,” http://eugenmed.eu/index.php/ meetings/2014-11-12-14-40-16/workshop-4.
21. The European Institute of Women’s Health (EIWH), 2015, Sex and gender in medicines regulation, https://eurohealth.ie/2015/05/11/sex-and-gender-in-medicines-regulation/.
22. Van Calsteren K, Gersak K, Sundseth H, Klingmann I, Dewulf L, Van Assche A, Mahmood T, 2016 “Position statement from the European Board and College of Obstetrics & Gynaecology (EBCOG): The use of medicines during pregnancy – call for action,” Eur J Obstet Gynecol Reprod Biol, 189-91. doi: 10.1016/j.ejogrb.2016.04.004.