Based on the EMA Guideline on Good Pharmacovigilance Practices (GVP) Chapter P.III – Product- or Population-Specific Considerations III
February 2026
Introduction: The Ethical Imperative of Protecting Two Lives
The evaluation of the benefit-risk balance for medicinal products used during pregnancy or breastfeeding represents one of the most complex and ethically sensitive areas in pharmacovigilance. Unlike the general population, every safety decision in this context must consider not one, but two interconnected lives—the mother and her child, whether exposed in utero or via breast milk .
The thalidomide tragedy of the 1960s fundamentally changed how the world views medication use during pregnancy, leading to decades of restrictive policies that, while well-intentioned, have created a new challenge: pregnant and lactating women remain “therapeutic orphans,” systematically excluded from clinical trials despite the reality that most will require medication during pregnancy or while breastfeeding .
This article provides a comprehensive medical overview of pharmacovigilance in pregnant and breastfeeding women, based on the recently finalized European Medicines Agency (EMA) Guideline on Good Pharmacovigilance Practices (GVP) Chapter P.III, which came into effect on February 9, 2026. We integrate insights from global regulatory frameworks, including the U.S. FDA’s Pregnancy and Lactation Labeling Rule (PLLR), and explore the scientific, clinical, and operational dimensions of medication safety in these special populations .
Section 1: The Unique Challenge of Pharmacovigilance in Pregnancy and Lactation
1.1 The Data Gap at Marketing Authorisation
At the time a medicinal product receives marketing authorisation, safety data regarding its use in pregnancy and breastfeeding are almost always limited or absent. This gap exists because:
- Pregnant and breastfeeding women are routinely excluded from clinical trials due to ethical and liability concerns
- Non-clinical animal studies provide only indirect evidence of potential human reproductive toxicity
- Knowledge of adverse reactions in the embryo/fetus is often extrapolated from other active substances with similar pharmacological properties, though “evidence of absence of harm for one active substance cannot be fully extrapolated to other active substances of the same class” (GVP P.III.A.1.1)
The 2025 TransCelerate survey of major pharmaceutical companies confirmed that post-approval activities—including pregnancy registries, database studies, and enhanced pharmacovigilance—remain the primary sources of safety information for this population, often taking years to generate meaningful data .
1.2 The Scope of Medication Use in Pregnancy and Lactation
Despite these data gaps, medication use during pregnancy and breastfeeding is common:
- Most pregnant women are prescribed at least one medication during pregnancy
- Most breastfeeding individuals take at least one prescription drug, despite limited safety data for many products
- Conditions requiring continued treatment during pregnancy include asthma, autoimmune disorders, diabetes, epilepsy, hypertension, HIV, psychiatric disorders, and thromboembolic events
This creates a therapeutic dilemma: healthcare providers must make prescribing decisions with incomplete information, balancing maternal health needs against potential fetal or infant risks.
Section 2: Physiological Changes and Susceptible Periods
2.1 Pregnancy-Induced Changes in Pharmacokinetics and Pharmacodynamics
Pregnancy induces profound physiological changes that alter drug disposition and response:
| Physiological Change | Effect on Drug Handling | Clinical Implication |
|---|---|---|
| Increased plasma volume | Lower drug concentrations | May require dose increases |
| Increased renal blood flow and GFR | Enhanced renal clearance | Reduced exposure to renally excreted drugs |
| Altered hepatic enzyme activity | Variable effects on metabolism | Unpredictable drug levels |
| Changes in protein binding | Increased free drug fraction | Potential for toxicity |
| Placental transfer | Fetal exposure | Need to assess fetal risk |
These changes may result in reduced treatment efficacy or increased systemic exposure leading to maternal and/or fetal toxicity, particularly for drugs with a narrow therapeutic window (GVP P.III.A.1.2).
2.2 Susceptible Periods for Adverse Pregnancy Outcomes
The timing of medication exposure during pregnancy critically determines the nature and severity of potential adverse outcomes. Susceptibility varies at different stages of embryonic and fetal development (GVP P.III.A.1.3):
| Gestational Period | Developmental Events | Potential Adverse Outcomes |
|---|---|---|
| Week 0–3 + 6 days | Pre-organogenesis, implantation | Early pregnancy loss |
| Week 4–11 + 6 days (end of week 4 through end of week 12) | Organogenesis—formation of major organ systems | Major congenital anomalies; each organ has its specific critical period, generally shorter than 8 weeks; potential impact on brain development manifesting during childhood |
| Week 12 (+0) to delivery | Fetal growth and functional maturation | Structural anomalies (some organ systems remain sensitive); growth restriction; permanent or transient functional birth defects |
| Late pregnancy or during delivery | Preparation for extrauterine life | Reversible or irreversible physiological impacts: premature ductus arteriosus closure, acute renal insufficiency, pulmonary hypertension, sedation, withdrawal reactions |
Critical Consideration: If exposure to an active substance mostly results in early pregnancy loss, fetal death, or stillbirth, then evaluating only the frequency of birth defects would underestimate the true embryo-fetal risk. Moreover, perturbations during critical developmental periods may lead to functional or neurodevelopmental impairments that are not apparent at birth but become evident as the child grows, necessitating longitudinal assessment (GVP P.III.A.1.3).
2.3 Adverse Reactions in Neonates/Infants Following Breast Milk Exposure
For breastfed infants, adverse reactions can occur when medications excreted into breast milk accumulate due to the infant’s immature elimination capacity. Pharmacokinetic data relating to maternal levels, breast milk concentrations, and infant exposure (including bioavailability) are essential for risk assessment .
Section 3: Regulatory Framework and Terminology
3.1 Key Definitions (GVP P.III.A.2)
Understanding pharmacovigilance in this context requires precise terminology:
| Term | Definition |
|---|---|
| Embryo | Stage from conception through end of implantation, including organogenesis, through the first 10 weeks of gestation |
| Fetus | Stage from 11th week of gestational age to birth |
| Neonate | From day of birth plus 27 days (pre-term or term) |
| Infant | 1 month (28 days) to 23 months |
| Child | 2 to 11 years |
| Miscarriage (Spontaneous Abortion) | Fetal death before 20 completed weeks of gestation |
| Stillbirth | Fetal death after 20 completed weeks of gestation |
| Termination of Pregnancy (TOP) | Deliberate interruption of pregnancy by medical or surgical means |
| TOPFA | Termination of Pregnancy for Fetal Anomaly |
| Pre-term birth | Birth before 37 completed weeks (<259 days) |
| Term birth | 37 completed to <42 completed weeks (259–293 days) |
| Low birth weight | <2,500 grams |
| Very low birth weight | <1,500 grams |
| IUGR | Intrauterine Growth Restriction—fetus does not achieve expected in-utero growth |
| SGA | Small for Gestational Age—weight below 10th percentile for gestational age |
| Congenital anomaly | Structural or functional anomaly of organs, systems, or body parts |
| Major congenital anomaly | Significant medical, social, or cosmetic consequences; typically requires intervention |
| Teratogen | Agent capable of interrupting or altering normal development, potentially causing congenital anomaly or death |
Prevalence Definitions for Congenital Anomalies:
- Live birth prevalence: Live births with anomalies / All live births
- Birth prevalence: Live births + stillbirths with anomalies / All live births + stillbirths
- Total prevalence: Live births + stillbirths + TOPFA with anomalies / All live births + stillbirths + TOPFA
3.2 The FDA Pregnancy and Lactation Labeling Rule (PLLR)
In the United States, the PLLR (effective June 2015) fundamentally changed how prescription drug labeling communicates information for pregnancy and lactation :
- Removed pregnancy letter categories (A, B, C, D, X)—which were often misinterpreted as a grading system
- Created three detailed subsections:
- 8.1 Pregnancy: Includes Risk Summary, Clinical Considerations, Data, and information about pregnancy exposure registries
- 8.2 Lactation: Provides information on drug levels in breast milk and potential effects on breastfed infants
- 8.3 Females and Males of Reproductive Potential: Includes pregnancy testing, contraception recommendations, and infertility information
The FDA has further studied how healthcare providers use lactation information, finding that while providers prefer concise summaries, they often modify prescribing decisions after reviewing detailed narrative data .
Section 4: The Pharmacovigilance Framework for Pregnancy and Lactation
4.1 Risk Management Plan (RMP) Considerations
For medicinal products that may be used during pregnancy or breastfeeding, the RMP must address these populations appropriately (GVP P.III.B.1):
| RMP Category | Application to Pregnancy/Lactation |
|---|---|
| Missing Information | Use in pregnancy or breastfeeding when data are insufficient |
| Important Identified Risk | When evidence establishes a causal association with adverse pregnancy outcomes |
| Important Potential Risk | When animal data or class effects suggest possible harm, but human data are lacking |
4.2 When to Prioritize Follow-up Data Collection
Systematic collection of information on medication exposure during pregnancy is good practice, but certain situations warrant particular attention (GVP P.III.B.1.1):
- Conditions requiring treatment for maternal and/or fetal benefit, where discontinuation would increase risk for both:
- Asthma, autoimmune disorders, diabetes, epilepsy, hypertension, thyroid disorders
- Infections, intoxications, malignant diseases, severe psychiatric disorders
- Thromboembolic events, transplant rejection prevention
- Common symptoms treated during pregnancy even when not strictly necessary:
- Constipation, fatigue, allergic symptoms, common cold, fever, mood alterations
- Nausea/vomiting, pain (including OTC products)
- Medicinal products from classes with known or suspected embryo-fetal toxicity based on case reports or animal studies
- New classes or new modes of action
4.3 Post-Authorisation Safety Studies (PASS)
When safety data are limited, PASS may be warranted to better characterize risks. Study design must account for the unique challenges of pregnancy research .
4.3.1 Types of Epidemiological Studies
| Study Type | Objective |
|---|---|
| Drug Utilisation Studies (DUS) | Estimate extent of exposure in women of childbearing potential, pregnant, and breastfeeding women; describe user characteristics and patterns |
| Drug Safety Studies | Assess specific adverse outcomes following exposure, accounting for confounding by indication |
| RMM Effectiveness Studies | Evaluate whether risk minimisation measures are achieving their intended impact |
4.3.2 Data Sources
Multiple data sources are available, and often need to be combined across countries to achieve adequate study size :
- Pregnancy registries: Can be disease-based (preferred) or product-specific
- Healthcare databases: Electronic health records, claims data
- Existing cohort studies: EUROCAT (European network of population-based registries for congenital anomalies)
- Teratology information services: ENTIS (European Teratology Information Services) provides clinical-pharmacological network support
Regulatory preference: The EMA encourages disease registries over medicinal product-specific registries, and the FDA encourages multi-sponsor collaborations to pool resources and accelerate data collection .
4.3.3 Key Methodological Considerations
Study designs must address:
- Pregnancy exposure windows to be studied
- Method for determining gestational age
- Handling of competing endpoints (miscarriage, stillbirth, TOPFA)
- Selection of appropriate comparators (unexposed, active comparator, timing-based contrasts)
- Confounding by indication—the underlying maternal disease may itself affect pregnancy outcomes
- Recall bias in retrospective data collection
4.4 Signal Management
Detecting signals of teratogenicity or other pregnancy-related risks is challenging due to :
- Low baseline incidence of specific congenital anomalies (e.g., 0.224 per 10,000 births for some conditions)
- Variations in reporting practices
- Complexity of pregnancy-related symptoms
- Delayed onset of some outcomes (e.g., neurodevelopmental disorders)
Tools for Signal Detection (GVP P.III.B.6):
| Tool | Application |
|---|---|
| SMQ “Pregnancy and Neonatal Topics” (1st level) | Broad retrieval of pregnancy outcomes |
| EMA EudraVigilance Pregnancy Algorithm | More efficient identification of pregnancy-related cases with 90% positive predictive value (vs. 54% for SMQ PNT) |
| SMQ “Lactation Related Topics” | For adverse outcomes due to breast milk exposure |
Important: A signal of a possible teratogenic effect (e.g., a cluster of similar abnormal outcomes) must be notified immediately to competent authorities.
Section 5: Individual Case Safety Reports (ICSRs) in Pregnancy and Lactation
5.1 Special Handling Requirements
Suspected adverse reactions following in utero or breast milk exposure are subject to ICSR reporting requirements, with specific considerations (GVP P.III.B.2):
5.1.1 Coding Principles
| Element | Requirement |
|---|---|
| Reaction coding | Comply with MedDRA Points to Consider; use HLT “Exposures associated with pregnancy, delivery and lactation” for all exposure cases, even without adverse reactions |
| Route of administration (maternal) | Standard route coding |
| Route of administration (breastfeeding) | Code as “transmammary”; use PT “Drug exposure via breast milk” in reaction section |
| Outcome coding (congenital anomalies) | Use “Not recovered/not resolved/ongoing” (ICH-E2B(R3) E.i.7) |
| Pregnancy outcome coding | Reflect latest available information; separate coding for exposure vs. reaction |
5.1.2 Essential Information to Collect
- Prospective vs. retrospective case: Was exposure data collected before or after pregnancy outcome known?
- Gestational age at exposure and at reaction observation
- Timing of exposure: Trimester, weeks, days
- Method of gestational age assessment (LMP, ultrasound)
- Exposure details: Dose, duration, indication
- Other potential causes: Medication history, infections, occupational exposures, family history of anomalies, maternal disease, lifestyle factors
- Examination results: Fetal ultrasound, amniocentesis, laboratory tests
5.2 Submission of ICSRs
The GVP provides clear guidance on how to submit cases involving pregnancy exposure:
| Situation | Case Creation |
|---|---|
| Adverse reactions in both mother and child/fetus | |
| Miscarriage/Spontaneous abortion | 1 case (mother) |
| Fetal death without malformation info | 1 case (mother) |
| Fetus with birth defects | 2 linked cases (mother + fetus) |
| Congenital anomaly/adverse reaction in neonate/infant/child | 2 linked cases (mother + baby) |
| No adverse reaction in fetus/neonate/infant/child | 1 case (mother), stating pregnancy outcome |
| No adverse reaction in mother, adverse reaction in child/fetus | |
| Miscarriage/Spontaneous abortion | 1 case (mother) |
| Fetal death without malformation | 1 case (mother) |
| Fetus with birth defects | 1 case (fetus) |
| Birth defects/adverse reaction in neonate/infant/child | 1 case (baby) |
| Multiple births | 1 case for each birth with a suspected adverse reaction; link cases |
5.3 Pregnancy Follow-up Questionnaires
Standardized questionnaires (see GVP P.III Appendix 1) should be used to collect comprehensive information, covering :
- Maternal information: Demographics, obstetrical history, medical history, risk factors
- Current pregnancy: LMP, gestational age, fertility treatment, co-medications, complications
- Delivery details: Date, mode, complications
- Neonatal/infant/child information: Birth outcomes, physical examination, congenital anomalies, developmental assessment
- Paternal information (when relevant)
- Embryo/fetal information for TOP, TOPFA, miscarriage, stillbirth
Recommended follow-up time points:
- During pregnancy (as relevant)
- At birth
- 3 months after delivery
- 12 months after birth (and beyond for specific concerns)
Section 6: Periodic Safety Update Reports (PSURs)
For medicinal products with pregnancy-related safety concerns, PSURs must include (GVP P.III.B.3):
6.1 Required Information
| Section | Content |
|---|---|
| Estimated exposure and use patterns | Age- and sex-specific data; cumulative exposed patients; method of exposure calculation |
| Summary of safety concerns | Safety during pregnancy and breastfeeding (even if not specified as a concern) |
| Findings from non-interventional studies | Results from dedicated studies |
| Signal and risk evaluation | Spontaneous reports of adverse reactions in embryo/fetus/neonate/infant/child following in utero or breast milk exposure; integrated interval and cumulative assessment |
| Cumulative data | Pregnancy outcomes presented in standardized table format |
6.2 Pregnancy Outcome Table Format
The GVP specifies a detailed table format for reporting ICSRs in PSURs, organizing cases by:
- Pregnancy outcome type (ectopic pregnancy, miscarriage, TOPFA, TOP, stillbirth, live birth)
- Timing of exposure (before conception, 1st trimester, after 1st trimester, throughout pregnancy, unknown)
- Prospective vs. retrospective cases
- Congenital anomaly details for TOPFA and stillbirth cases
Section 7: Breastfeeding: Special Considerations
7.1 The Lactation Data Gap
At the time of marketing authorisation, data on risks for breastfed neonates/infants are usually not available. Factors that help assess safety include :
- Pharmacokinetic data from animal or human lactation studies
- Bioavailability information
- Actual exposure data from breastfed infants
7.2 Clinical Breastfeeding Studies
When use among breastfeeding women is anticipated and no human data exist, pharmacokinetic studies in lactating women should be considered (GVP P.III.B.4.2.4):
- Collect breast milk samples for measurement of active substance levels
- Estimate relative infant dose to support risk assessment
- Collect data on milk production/composition if clinically relevant
7.3 FDA Research on Lactation Labeling
Recent FDA research explored how healthcare providers use lactation information :
- Most providers were unaware of PLLR updates to lactation labeling
- Providers prefer concise summaries from apps, websites (LactMed, UpToDate), or colleague consultations
- Three headline types tested:
- “Safety concerns have been identified” → Most would not prescribe
- “Potential safety concerns have been identified” → Led to individual benefit-risk assessment
- “No safety concerns have been identified” → Most would support use
Key finding: While many providers make initial decisions based on concise summaries, they often modify those decisions after reviewing detailed narrative data, underscoring the need for accessible yet comprehensive information.
7.4 Signal Detection for Breastfeeding
For adverse outcomes due to breast milk exposure, use:
- SMQ “Pregnancy and neonatal topics” (1st level) to retrieve “Lactation related topics”
- SMQ “Lactation related topics” (level 2 narrow) for more precise retrieval
Section 8: Long-term Outcomes and Neurodevelopmental Considerations
8.1 The Challenge of Delayed Manifestation
Adverse outcomes resulting from in utero exposure may not be observed immediately after birth :
- Some effects manifest during childhood (e.g., neurodevelopmental disorders)
- Others may appear in adult life or even trans-generationally
8.2 Neurodevelopmental Outcomes
When assessing neurodevelopmental outcomes, consider:
- Varying timelines for motor and language skill development
- Different measurements needed at different developmental stages
- Follow-up may need to extend into preschool, school age, and adolescence
The decision to conduct long-term studies should be based on:
- Biological plausibility
- Non-clinical data
- Clinical data (anomalies, prematurity, growth retardation)
- Pharmacological properties
- Signals regarding adverse long-term outcomes
8.3 Resources for Long-term Assessment
Section 9: Risk Minimisation and Communication
9.1 Risk Minimisation Measures (RMM)
Information on pregnancy and lactation risks must be included in product information. Additional RMM may include :
- Educational materials for healthcare providers and patients
- Safety advice materials
- Pregnancy prevention programs for known teratogens
- Information about pregnancy exposure registries
9.2 Safety Communication Objectives
Effective communication should enable :
- Women and healthcare providers to take informed therapeutic decisions
- Prevention of negative impacts on the child
- Promotion of adherence to RMM
- Support for informed choices regarding pregnancy while addressing maternal medical needs
- Prevention of unnecessary interruption of maternal treatment or breastfeeding
9.3 The Risk-Benefit Dialogue
For breastfeeding women, the conversation must balance:
- Benefits of breastfeeding for infant and mother
- Risks of medication exposure through breast milk
- Risks of untreated maternal disease
- Available data (or lack thereof)
Clinical takeaway: In the absence of robust clinical data or clear safety findings, a detailed benefit-risk discussion with the breastfeeding individual is essential, acknowledging the limitations of current knowledge .
Section 10: Future Directions and Unmet Needs
10.1 The Need for Harmonized Guidance
A 2025 review by TransCelerate and multiple pharmaceutical companies identified the need for harmonized global guidance on studying medication use in pregnancy . Current differences between regions create challenges for:
- Planning research programs
- Interpreting study results
- Implementing consistent risk minimisation
10.2 Priority Areas for Future Research
10.3 The Ethical Imperative
As the GVP states: “The overall aim is to provide patients and healthcare professionals with information that can support therapeutic decision-making about using medicinal products during pregnancy or breastfeeding.”
Achieving this aim requires:
- Proactive data collection throughout the product lifecycle
- Rigorous signal detection and evaluation
- Clear communication of both known risks and remaining uncertainties
- Collaboration among regulators, industry, researchers, and patients
Conclusion: A Shared Responsibility
Pharmacovigilance in pregnant and breastfeeding women is a shared responsibility among:
The recently finalized EMA GVP Chapter P.III provides a comprehensive framework for fulfilling these responsibilities. By integrating rigorous science with ethical patient-centered care, we can gradually close the evidence gap and ensure that pregnant and breastfeeding women—and their children—receive the safe, effective treatments they deserve.
The ultimate goal: Not to eliminate all risk, but to understand it, communicate it clearly, and manage it effectively, so that therapeutic decisions can be made with confidence and compassion.
References
- European Medicines Agency. Guideline on good pharmacovigilance practices (GVP): Product- or population-specific considerations III: Pregnant and breastfeeding women and their children exposed in utero or via breastmilk. EMA/653036/2019. February 2, 2026.
- U.S. Food and Drug Administration. Pregnancy and Lactation Labeling Resources. March 9, 2025. Available from: https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-resources
- Alexe A, Wurst K, Balramsingh-Harry L, et al. Points to Consider on the Use of Medicines in Pregnancy Throughout the Product Lifecycle Based on Global Regulatory Guidance. Ther Innov Regul Sci. 2025 May;59(3):462-470.
- Xtalks. Multi-sponsor Pregnancy Exposure Registries: Physician, Scientific Advisory and Industry Insights. August 2024. Available from: https://xtalks.com/webinars/multi-sponsor-pregnancy-exposure-registries-physician-scientific-advisory-and-industry-insights/
- NHS Digital. EUROCAT: European network of population-based registries for congenital anomalies. February 2024. Available from: https://production-like.nhsd.io/ndrs/our-work/ncardrs-partnerships/eurocat
- Scantamburlo Fernandes MF, Alexe A, Weber M, et al. Post-approval Activities Providing Data on the Safety of Medication Use During Pregnancy and Lactation-A TransCelerate Perspective. Ther Innov Regul Sci. 2025 Mar 16. Online ahead of print.
- U.S. Food and Drug Administration. Healthcare Providers’ Use of a Concise Summary to Prescribe for Lactating Patients. November 2024. Available from: https://www.fda.gov/drugs/spotlight-cder-science/healthcare-providers-use-concise-summary-prescribe-lactating-patients
- Syneos Health. Multi-sponsor Pregnancy Exposure Registries: Physician, Scientific Advisory and Industry Insights. October 2024. Available from: https://jp.syneoshealth.com/insights-hub/webinar-multi-sponsor-pregnancy-exposure-registries-physician-scientific-advisory-and
- ENTIS. European Teratology Information Services: Centers. Available from: http://www.entis-org.eu/centers
