Use of Therapeutics in Pregnancy and Lactation
Use of Therapeutics in Pregnancy and Lactation
This theme issue of Pharmaceutical Research is dedicated to drug research and therapy in pregnant and breastfeeding woman. Enthusiasm for studying drug safety and toxicity in these patients (and in their children) has risen over the past decade. Yet, the accumulation of data is slow. A combined effort of industry, regulators, academia and clinicians can promote the treatment of these populations, as discussed in detail in this issue.
Pregnant and breastfeeding women are orphan
populations with regard to drug safety and efficacy, because they
have been historically excluded from clinical trials. Less than
3% of prescription medications approved by the U.S. Food
and Drug Administration (FDA) between 2000 and 2010
had enough information to determine their teratogenic risk.
The mean time necessary to assign a more precise risk to
treatments initially judged to have an Bundetermined^ risk is
27 years (
). Furthermore, new findings may emerge on drugs
that have been on the market for decades with relatively
established risk estimation. For instance, valproic acid was first
1 Institute of Drug Research, School of Pharmacy, The Hebrew University,
2 Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The
Hebrew University, Ein Kerem, Jerusalem, Israel
approved for the treatment of epilepsy in 1967 and its
structural teratogenicity has been recognized in the early 1980s.
Three decades later, findings from the Neurodevelopmental
Effects of Antiepileptic Drugs (NEAD) prospective study
indicated that children exposed to this drug in utero had IQ scores
6–10 points lower at ages 3 years (
) and 6 years (
compared to children exposed to other antiepileptic drugs.
Valproic acid use during pregnancy has also been associated
with other worse neurobehavioral outcomes, including
increased risk of autism spectrum disorders of the offspring
). These observations raised legal and ethical issues and
led to changes in recommendations and guidelines (
in prescribing patterns of this drug for women of childbearing
Given the consistent lack of safety information, combined
with concerns among pregnant women following the
thalidomide and other therapeutic disasters, it is not surprising that
these patients avoid drugs. A recent study in the U.S. of
approximately 1.9 million pregnancies found that the median
prevalence ratio of use of 34 drugs was 0.2 comparing
pregnant to nonpregnant periods, further increasing the challenges
of studying the safety of these medications (
). Likewise, data
on safety during lactation are scarce for most approved
The articles in this theme issue of Pharmaceutical Research
cover a broad spectrum of topics related to the
pharmacokinetics and pharmacodynamics of drugs in pregnancy and
lactation. Drug development and pharmacotherapy in pregnant
and breastfeeding women are a special challenge not only
because of the potential risk to the child, but also because
pharmacokinetics and drug effects on the mother may change
during pregnancy (and again postpartum, in parallel with
initiation of breastfeeding). In this context, Koren and Pariente
present a review of pregnancy-induced pharmacokinetic
changes and their clinical implications (
). They describe
pregnancy-related alterations in drug absorption, distribution
and elimination as well as the silent pharmacokinetic
parameter, drug adherence. Also highlighted is the absence of
pregnancy-targeted dose schedules, especially when
compared to existing dose modifications, for example in renal
failure or in young children.
In addition to maternal pharmacokinetics, an important
determinant of fetal exposure is the placenta. The placenta is
involved in the pathophysiology of many adverse pregnancy
), but potential adverse placental drug effects have
been generally overlooked and are only now beginning to be
recognized. Our review of placental pharmacokinetics and
pharmacodynamics describes the current knowledge on the
transfer of small molecules, biologics, and nanoformulations
across the placenta and the effects of these therapeutics on
the placental barrier itself (
The developing brain is protected by additional
distributional barriers, namely the blood-brain barrier (BBB) and the
blood-cerebrospinal fluid barrier (BCSFB). Ghersi-Egea,
Saudrais, and Strazielle review the development of these
barriers and describe factors that can affect cerebral drug
). Also discussed is the higher vulnerability of the
developing brain to insults of various types and the potential
impact of such injuries on cerebral drug distribution. The
authors additionally point to the need for thorough
investigation of the developmental pattern of transcytosis mechanisms,
which are relevant for newer generation drugs and drug
Two articles in this issue provide clear examples of the still
expanding knowledge on adverse fetal outcomes of drugs
that have been in clinical use for many years. The review by
Ornoy addresses a gap in literature by describing the available
information on treating attention deficit hyperactivity disorder
in pregnant and breastfeeding women (
). Equally important,
the fields in which knowledge is not available are highlighted.
For example, methylphenidate crosses the placenta and
achieves significant cerebral concentrations in experimental
animal models, but data on the neurodevelopmental effects
of methylphenidate in humans are scarce. The other article,
by Ziv, Perlman, Masarwa, Ziv and Matok, is a systemic
review and meta-analysis of pregnancy outcomes following
exposure to quinolone antibiotics (
). Reports on quinolone
toxicity to connective tissues in animals, together with the
limited information on the safety of quinolones during pregnancy,
have led to restricted use of these drugs in young children,
neonates, and pregnant women. The meta-analysis presented
by Ziv et al. included twelve studies and found that based on the
available data, first-trimester exposure to quinolones is not
associated with adverse pregnancy outcomes, thus suggesting
that restrictions on prescribing quinolones during early
pregnancy may be reconsidered. This study demonstrates how the
power of meta-analysis can be harnessed to provide better
information on drug safety in pregnant women.
Finally, a review by Anderson describes the state-of-the-art
of studying drug pharmacokinetics and pharmacodynamics in
breastfeeding mothers and their infants. Exposure of the
nursing infant to maternal drugs is overall lower as compared to
exposure during pregnancy and teratogenicity is not a
concern. Safety in lactation can be more directly assessed by
sampling of breast milk and, in some cases, infant blood (
review elaborates the factors that affect the passage of drugs to
breast milk and their pharmacokinetics in the nursing infant,
models and designs of lactation studies, and regulatory issues.
A special focus is put on modeling of drug passage to breast
milk and to the nursing infant, with examples of the utility and
limitations of the various modeling approaches.
The growing need for understanding, or even predicting,
drug efficacy in pregnancy and lactation led regulatory
agencies to change their policies and issue new research initiatives,
including establishment of postmarketing pregnancy registries
and collaborative research networks (
approaches that are especially suitable for the sparse data
available from studies in pregnant and breastfeeding women are
being increasingly used. In addition, new drug and biological
product labeling standards, the Pregnancy and Lactation
Labeling Rule (PLLR), became effective on 30 June 2015
). The new system is a more descriptive report that
summarizes the data about the risks and any other relevant
information on drug use in pregnancy and lactation. Yet, to
enhance the transparency and impact of this system, it has to be
supported by data provided by industry and clinicians. To this
point, in the era of personalized and stratified medicine,
pregnant and breastfeeding women (and their children) should be
recognized as special populations that can be included in
research in order to address their needs. As with other special
populations, the data gained through such studies can provide
new opportunities for the development of drugs and drug
delivery systems for these patients. In the meantime,
pharmacometric approaches and meta-analyses can support
decision-making by healthcare professionals.
The author has no commercial or financial relationships
that could be construed as a potential conflict of interest.
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