Keywords
drug safety - pregnancy - lactation - pharmacokinetics - drug surveillance
Although a large number of pregnant and lactating women receive prescription drugs,
over-the-counter (OTC) medications, and supplements, many knowledge gaps persist concerning
the safety and efficacy of these therapies. Consequently, there is wide variability
in the advice women receive concerning medication use during pregnancy and lactation.
To address this, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Society for
Maternal-Fetal Medicine (SMFM), the American College of Obstetricians and Gynecologists
(ACOG), and the American Academy of Pediatrics (AAP) convened a group of experts to
a workshop to review the “current” state of the clinical care and science regarding
medication use during the perinatal period. These groups were also charged with suggesting
guidance for practitioners as well as identification of research gaps. This manuscript
provides a summary of the opinions provided by the expert panel.
The Centers for Disease Control and Prevention (CDC) reports that the diagnosis of
prepregnancy chronic health conditions are on the rise in the United States.[1]
[2]
[3] These conditions include cardiovascular disease, metabolic disorders, mental health
disorders, and respiratory diseases.[4]
[5]
[6]
[7] These trends could be the result of improved modalities for diagnosing and treatments.[8]
[9]
[10] Because most interventions to manage these conditions employ the use of pharmacologic
products that have not been well studied in pregnant and lactating women, the true
risks and benefits of such interventions remain speculative. Furthermore, Mitchell
et al performed a retrospective study of more than 19,000 women from two case control
studies that enrolled patients from 1976 to 2008, and reported that approximately
90% of women were taking at least one medication, either prescription or OTC, during
their pregnancy.[11] About 7 in 10 women were taking one or more prescription medications during their
pregnancy with almost one-third of women using four medications.[11] In addition, medication use in the first trimester increased by 62.5% over the study
period. The most dramatic increase in prescription medication seen in this study was
women who were exposed to antidepressants from 1988 to 1990 (< 1%) and the striking
increase and peak at 7.5% during the study period of 2003 to 2008.[11] According to Werler et al, two case-control studies demonstrated that acetaminophen
was used at least 65% of the time, whereas ibuprofen and pseudoephedrine exposure
during pregnancy occurred in approximately one in six women.[12] There have been very few studies examining the risks of pregnancy and fetal outcomes
after exposure to OTC medications as well as prescription drugs.
Professional entities including SMFM, ACOG, and AAP strongly advocate that women breast-feed
their infants because of its numerous maternal and neonatal health benefits. Breast-feeding
rates have increased approximately 2% per year between 1996 and 2001.[13]
[14] Stultz et al studied 46 women who provided medication history during their pregnancy
and while they breast-fed their infants.[15] In this cohort, there was a significant increase in both prescription and OTC medication
use during lactation compared with when they were pregnant. More than 70% of women
were taking medications that were potentially unsafe, or had unknown safety profiles.
Anderson et al evaluated 100 articles between 1966 and 2002 to examine possible adverse
outcomes in neonates due to their exposure to maternal medication(s) during breast-feeding.[16] These authors reported that 47% of adverse outcomes in the neonates as “possibly”
linked to medication exposure during breast-feeding; 53% as “probably” linked and
no infant-related deaths were associated with medications.[16] However, there is little research focusing on understanding the quantity of medication
and their chemical effects on neonates during breast-feeding.
Only 5% of the 213 new pharmaceuticals approved by the Food and Drug Administration
(FDA) between 2003 and 2012 contained human data in their pregnancy section; almost
one-half did not have any safety information concerning the medication use for lactating
women.[17] Because of the lack of studies on specific drugs in pregnancy and lactation, the
efficacy and dosing data are generally extrapolated from studies from adult subjects
(men and nonpregnant women) and safety data are collated from the FDA-mandated postmarket
surveillance. Such data often come from the use of pregnancy-exposure registries that,
while useful, are greatly limited by inherent design biases.
During the workshop, the expert panel focused on the “current” state of practice and
reviewed available data on select drugs in pregnancy. The group discussed what providers
optimally should know about the pharmacokinetics of drugs particularly given the physiologic
changes that occur in the course of pregnancy and postpartum, as well as the time
of greatest vulnerability in terms of drug effects on the fetus and newborn. There
was evidence presented about the interaction of drugs and breast milk, indicating
that some assumptions could be made about the efficiency with which certain drugs
may cross into breast milk and potentially pose further exposure risks to the neonate.
Potential lessons learned from the pediatric experience with enrolling children in
drug trials to enhance knowledge in this unique population and the robust safety systems
in place to monitor vaccines were reviewed. The presentations and discussions from
the 2-day workshop are summarized here.
Pharmacokinetics of Drugs in Pregnancy
Pharmacokinetics of Drugs in Pregnancy
An extensive discussion of these pharmacokinetic principles were reported at the workshop
and are detailed in a subsequent publication by Feghali et al.[18] In brief, the pharmacokinetics of a given drug describes the processing of the drug
through the body and incorporates several components, including the drug's absorption,
distribution, metabolism, elimination, and transport. Usually it is the bioavailability
of drug, the amount of drug that is able to target the tissue, which is critical in
determining how efficacious the drug will be. This depends on a combination of factors
including properties of the drug as well as properties of the host. For example, the
bioavailability of orally administered medications is affected by absorption across
the intestinal epithelium and by first-pass metabolism in the intestine and liver.
All these factors are more variable in pregnancy because the stomach pH, transit time,
metabolism, uptake, and efflux transport processes are altered during pregnancy, thereby
potentially changing the drug's bioavailability. Conversely, the uptake of the same
drug given intravenously or intramuscularly may be less variable than when orally
administered, but it remains different in the pregnant state compared with the nonpregnant
state in which there is increased cardiac output and increased intestinal blood flow
leading to increased overall absorption. In addition to these changes, drug distribution
is different in pregnancy in which the distribution of a given drug is altered depending
on tissue perfusion, binding, lipid solubility, and plasma protein binding. Again,
the expanded plasma volume experienced during pregnancy and the fact that a proportion
of a compound may cross the placenta may influence hydrophilic drugs causing lower
than anticipated plasma concentrations in the pregnant woman. Similarly, with lipophilic
drugs, the expanded maternal body fat during pregnancy may alter the plasma concentration
and resulting efficacy of these medications. Drug metabolism, the chemical process
that converts the drug into its active form, is also heavily influenced by the physiologic
changes that occur in pregnancy and certainly influence the activity of a given drug.
Drug elimination is another critical component to the bioavailability of that agent.
For example, although the glomerular filtration rate is 50% higher in pregnant than
in nonpregnant states and is relatively stable throughout gestation, drugs that are
cleared by the kidney act variably, likely due to changes in renal tubular transport.
Finally, an area of great importance is drug transport. The fetal-placental compartment
and the transport proteins within it greatly influence the amount, timing, and degree
of drug exposure for the developing fetus, and how this is different throughout gestation
is at least in part related to the variable expression of fetal damage seen with some
medications.
Fetal Development and Vulnerability
Fetal Development and Vulnerability
Human embryogenesis, the beginning stages of cell division and cell differentiation
of the human embryo, depends on the stem cells ability to divide, migrate, and specialize.[17] This intricate process results in the susceptibility and risk of teratogenicity.
The teratogenic period can be particularly severe from day 31 after the last menstrual
period in a 28-day cycle to 71 days from the last period.[19] In this timeframe, teratogens have the potential to influence malformations that
are noticeable at birth and exposure to teratogens prior to day 31 may produce an
“all-organ effect” in which the conceptus does not survive or survives with anomalies.
It is also possible that the fetus survives without anomalies due to the regeneration
of any damaged tissue.[19] In addition to the developmental susceptibility, it is important to note that functional
maturation begins in utero and continues into the postnatal period and also remains
a time of potential harm. There is differential susceptibility by trimester of pregnancy
and organ system. There are several examples where specific fetal malformations are
caused by exposure to medications during a critical time in pregnancy such as thalidomide,
angiotension-converting enzyme inhibitors, and certain antiepileptic medications.[20]
[21]
[22]
The evaluation of the teratogenic risk of a given drug is complex. Risk assessment
is ultimately based on animal, human, and pharmacologic data when available, and scientific
evidence of teratogenicity relies on nonclinical data, drug class characteristics,
biologic plausibility of exposure, impact of maternal disease or condition, and human
data. Animal toxicology studies are designed specifically to identify hazards and
potential toxic effects on targeted organs. These animal studies allow assessment
of potential hazards that cannot be assessed in human clinical trials; however, they
are limited in their applicability to humans. Some animal studies will include data
on male and female fertility, parturition, and lactation. There is also an assessment
of developmental toxicity, including mortality, dysmorphogenesis, alterations in growth,
and functional toxicity. Once the animal studies are reviewed, there is a “data integration
process” that then considers several factors, including, but not limited to, dose
response, rarity of adverse events, relative exposure, and cross species concordance.
However, the significant increase in medications used during pregnancy far outpaces
the body of knowledge for effects on the fetus.
Transfer of Drug in Human Breast Milk
Transfer of Drug in Human Breast Milk
There is limited information on most drugs used by breast-feeding women, which poses
challenges for women and their providers. Consequently, many providers will recommend
stopping a medication based on theoretical concerns about its safety for the neonate,[13] and this may lead to inadequately treated maternal disease. Information needed to
make decisions about medications and breast-feeding includes knowledge of the need
for the drug, the excretion of the drug into breast milk, the extent of oral absorption
of the drug by the neonate, the potential adverse effects on the neonate, and the
potential effect of the drug on lactation.[23]
[24] In addition, the infant's age is relevant and should be considered as adverse events
are rarer in infants older than 6 months. As in pregnancy, the biochemical properties
of a given drug are important elements such as drug ionization, molecular weight,
volume of distribution, lipid solubility, and protein binding, and they may influence
how much of the drug is excreted into breast milk. Furthermore, the half-life of the
drug and its oral bioavailability will influence how much is absorbed by the neonate.[25]
[26] One example of these complexities include emerging data demonstrating that there
are specific patient genotypes that influence the toxicity of given drugs. Stover
and Davis suggest that this area of pharmacogenomics holds promise in understanding
how neonates with in utero exposure to opioids may have different withdrawal patterns
based on specific polymorphisms.[27]
The main recommendations from the workshop were focused in the following areas: clinical
care recommendations, research gaps, and policy-related considerations.
The Expert Panel's Recommendations for Clinical Care
Clinicians and patients must make decisions incorporating the available data on the
maternal, fetal, and neonatal impact of disease; drug pharmacokinetics; maternal and
neonatal safety; limitations of the data sources; and guidelines from scientific bodies
if they exist. Panelists used examples of commonly used drugs such as acetaminophen,
pseudoephedrine, and antihypertensive agents to illustrate the risk-benefit analysis
undertaken to inform clinical practice.[28]
[29]
[30]
-
When clinicians utilize any drug or counsel women about OTC medications, there needs
to be a risk-benefit analysis, and when there are multiple options, the drug with
the most favorable benefit: risk ratio is utilized when considering the health of
both the mother and her baby.
-
There should be readily accessible information on drugs, which addresses the critical
components needed to make clinical decisions for clinicians to apply this risk-benefit
analysis. In the last 30 years, providers have relied heavily on the FDA's pregnancy
labeling that classified drugs as A, B, C, D, and X. However, these categories were
vague and often misleading. As of June of 2015, all new medications approved by the
FDA have a new pregnancy label with a narrative section that includes a risk summary,
clinical considerations, and supporting data. A section on lactation provides data
on the neonatal effects of the drug. In addition, the existence of drug registries
is displayed. While the new label should represent a vast improvement in providing
useful information, most drugs will not have been studied in pregnancy or during lactation,
which potentially leaves this new label just as ambiguous. Furthermore, this labeling
change pertains to drugs submitted to FDA review after June 2015, and the schedule
for revisions of old medications is unknown at this time.
-
Other resources for information on drug safety and dosing in pregnancy and lactation
include REPROTOX, TERIS, LactMed, and specific drug registries (up-to-date listing
can be found on the FDA Web site). Patient-specific education materials for select
commonly used medications are available on the CDC Web site, Treating for Two, and
using MothertoBaby fact sheets provided by the Organization of Teratology Information
Specialists. A recent clinical opinion by Temming et al provides a practical approach
to this decision-making process and includes a list of easily accessible on line resources.[31]
-
Women with chronic diseases requiring medication should have a preconception consultation
that would allow a thorough discussion of the impact of their disease on pregnancy,
as well as the risks and benefits of continuing a medication during pregnancy. When
written resources are available, drug information should be linguistically appropriate.
-
For women with complex medical conditions, the 6-week postpartum visit is an opportunity
for transition of care including reassessment of medications and use of contraception
if a medication is contraindicated in pregnancy or lactation.
The Expert Panel's Suggested Research Gaps
-
Focused studies are needed to develop specific approaches for improved communication
between providers and patients concerning the risks and benefits of the medications
intended to be used recognizing that medication use during the perinatal period should
be guided by shared decision making.
-
The pharmacokinetics of most drugs used during pregnancy remains a major knowledge
gap. Existing animal models need to be improved to address the mechanisms of actions
of drugs and drug toxicity in pregnancy, while assessing clinical outcomes.
-
Effective animal models and newer research techniques to study the use of medications
during lactation are lacking. Research using cell lines, trophoblast tissue preparations,
and placental perfusion models are useful to study placental transfer and metabolism.
In addition, computational models may be useful for simulations and integration of
data on fetal and placental compartments while “organ on a chip” models may be useful
to further explore the contributions of the placenta and fetus.
-
Specific information on medication efficacy is lacking due in part to limited accessibility
to tissues where these medications act. Functional imaging methods are noninvasive
tools that can provide functional and metabolic information in tissues in which medications
act, which can help assess medication efficacy. Use of these methods needs to be incorporated
in the study of medication use in the perinatal population.
-
Drug safety in the pregnant women has been narrowly focused on the first-trimester
exposure effects on the fetus leading to birth defects. However, many drugs may pose
a risk when used inappropriately (or inadequately) while treating conditions that
may adversely affect pregnancy outcomes. Thus, the safety issue has to be considered
in a broader context beyond teratogenesis to develop appropriate dosage strategies
taking into consideration the changing maternal physiology and chemical properties
of the drug. More studies on all aspects of safety of medications in pregnancy and
lactation are needed.
-
It is also critical to study long- term outcomes beyond birth defects, which may
include neurodevelopmental outcomes and functional impairments. This requires evaluating
drug effects beyond “the most vulnerable” time in fetal development, recognizing that
the brain continues to grow and mature beyond birth, and exposures during breast-feeding
may need equal attention. Drug studies focused on lactation should extend beyond 6
months and must focus broadly to include both preterm and term neonates. There is
an opportunity to collect more neonatal data on drugs by utilizing newer technologies
on smaller specimens and has been successful in the neonatal drug network.[29]
The Expert Panel's Policy-Related Considerations
-
Frequently, pregnancy is a contraindication for enrolling in clinical trials of new
medications. However, many panel members noted that it is unethical to exclude pregnant
women from drug trials, as the lack of critical data limits clinicians in making evidence-based
decisions. Furthermore, inadequate or inappropriate medication use has the potential
to increase maternal and fetal risks. These ethical and policy issues are summarized
in recent publications.[32]
[33] A systematic review by Coverdale et al that focused on randomized placebo-controlled
trials of antidepressant medication given to pregnant women concluded that such trials
were ethically justified.[34] The argument-based approach emphasizes an ethical framework in which scientific
studies should be following. The review endorsed the importance of conducting such
trials as they would assist in appropriate treatment and build confidence in the physician's
ability to prescribe antidepressant medication. Determining whether the impact on
fetal development is due to the drug versus the mood disorder itself is equally important.[34] Filling the knowledge gaps with well-designed studies could lead to new scientific
knowledge to address the pressing needs of pregnant women and the intricacies related
to medication use.[35]
-
Safety of medications administered during pregnancy is a major concern for clinicians
and patients. Utilizing the robust surveillance system created for vaccines, which
is continuously improving, provides an excellent model and starting point for drugs
as well. This safety system identifies and evaluates adverse events with a combination
of systems and partnerships ([Table 1]).[36]
-
The Vaccine and Medications in Pregnancy Surveillance System (VAMPSS), a postmarket
surveillance system for vaccines and drugs, conducts case control and prospective
cohort studies on certain drugs and vaccines in pregnancy.[37] Birth defects are the main outcomes for these studies, and there is currently a
need to broaden assessment to include long-term effects of these small numbers of
drugs (asthma medications) and vaccines (influenza and Tdap).
Table 1
Available safety monitoring systems
|
Vaccine Adverse Event Reporting System (VAERS)
|
A passive system whose data source includes patients, health care providers, and manufacturers
|
|
Post-Licensure Rapid Immunization Safety Monitoring (PRISM)
|
Collaboration that links national health insurance plans, immunizations registries,
and other partners, e.g., Centers for Medicare & Medicaid Services
|
|
Vaccine Safety Datalink (VSD)
|
Collaboration between the Centers for Disease Control and Prevention (CDC) and member
health care organizations
|
|
Clinical Immunization Safety Assessment (CISA) Project
|
Collaboration of seven medical research centers
|
|
Military Vaccine Agency
|
Department of Defense program that focuses on biologic threat preparedness, thus incorporating
medications as well as vaccines
|
|
VA Adverse Event Reporting System (ADERS)
|
VA surveillance system for vaccines and drugs
|
|
Pregnancy Exposure Registries
|
Passive system of specific drug exposures in pregnancy (postmarket surveillance)
|
|
Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS)
|
A postmarket safety surveillance of drugs and therapeutic biologic products
|
|
FDA—Sentinel Program (after Mini-Sentinel Pilot)
|
An active national electronic system to monitor safety of FDA-regulated products
|
|
Vaccine and Medications in Pregnancy Surveillance System (VAMPSS)
|
Nationwide postmarket surveillance system that is supported by public and private
partnership
|
Both the FDA and Congress attempted to improve appropriate pediatric drug information
and labeling through a series of legislative activities that included the 1994 Pediatric
rule, the 1997 FED Modernization Act(FDAMA), the 1998 Pediatric rule, the 2002 Best
Pharmaceuticals for Children Act (BPCA), and the 2003 Pediatric Research Equity Act
(PREA). Lessons learned from pediatric legislations suggest that similar obstetric
equivalents of PREA and BPCA could be valuable.[38]
[39]
Until the “future” state is reached, enhancements to our current system can lead to
important changes in data collection, which will improve clinical care for mothers
and babies. Collaboration between federal agencies around implementation of safety
system enhancements and existing data sources that could include pregnancy is needed.
The obstetric academic community and professional societies may collaborate as liaisons
to federal entities for topics dealing with research, practice, and surveillance of
drugs used during pregnancy and lactation.
In 2013, the CDC convened an expert group to develop a systematic approach to safer
medications use during pregnancy. This expert group proposed a flow diagram to support
expert review of available evidence on certain medications to provide consumers and
clinicians with vetted information to decide whether to use a given drug in pregnancy.[40] That proposed system has yet to be realized, and this most recent workshop further
outlines several critical needs in the areas of clinical decision making, research,
and policy. Pediatric clinicians recognized for decades that data on safety and efficacy
of drugs in pediatrics was lacking for similar reasons outlined previously where pediatric
medication data was extrapolated from adult studies. Their legislative experience
and focus on children being included in research have led to vast improvements in
this unique population. Similar efforts to improve the safety and efficacy of drugs
for pregnant and lactating women are critically important now given this growing unique
population.
