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400 Cobert’s Manual of Drug Safety and Pharmacovigilance
they too had taken DES, and Arthur Herbst and collabo-
rators confirmed the association between DES and CCA
in a case-control study in 1971.
Delayed Onset of Malignancy
(Long Latency)
The delay in the appearance of the adverse drug reac-
tion after the last dose (the latency period) of DES is
among the longest ever seen. The delay in detection has
several logical explanations:
The AE did not occur in the women who took DES
but in their female offspring exposed during the
critical window of vaginogenesis.
The AE was not visible in the female offspring at
birth.
The AE was not evident until after puberty during a
gynecologic examination.
Obstetric problems appeared only when a preg-
nancy occurred.
The spontaneous reporting consisted of a pub-
lication of the first series of cases and a case-control
study. The reported risk of developing CCA in DES-
exposed women is approximately 1 in 1,000 from birth
to 34 years of age. The risk increases rapidly from the
onset of puberty until the late teens and early twenties.
Subsequently, the risk drops dramatically, although a
few cases have been reported in women in their forties.
Other less serious but more frequent obstetric and gyne-
cologic problems in the DES-exposed progeny have also
been commented on in the medical literature:
Vaginal adenosis, cervical ectropion (normal, albeit
misplaced, columnar epithelium);
Structural anomalies, such as cervical hoods, hypo-
plastic, and T-shaped uterus;
Functional problems, such as decreased fertility,
ectopic pregnancy, spontaneous abortions (relative
risk, 92:1), and pre-term births (relative risk, 5:1);
Possible abnormalities in children of daughters
whose mothers received DES (i.e., third generation);
Benign malformations, such as small testicles and
epididymal cysts in males exposed in utero.
Actions Taken
In 1971, the FDA banned the use of DES in pregnant
women (FDA Drug Bulletin 1971). In the same year,
a registry was established at the University of Chi-
cago with Arthur Herbst as the chairperson. In 1978,
the national cooperative Diethylstilbestrol-Adenosis
(DESAD) Project was developed to identify and study
DES-exposed women with adenosis. In 1973, the US
National Institutes of Health notified medical schools
and gynecologic oncologists about increased cancer
risk. In 1977, France withdrew the obstetric indication.
A movement known as DES Action was created in the
United States, Canada, France, the United Kingdom,
and elsewhere. See its website.
In 1999, the US Congress directed the National
Cancer Institute to fund a 3-year DES National Edu-
cational Campaign housed at the Centers for Disease
Control and Prevention (CDC).
4
The third generation
(offspring of DES sons and daughters) are now being
followed for possible health issues related to DES use by
grandmothers. CDC maintains a complete website with
multiple links https://www.cdc.gov/des/index.html.
There are other examples of long-latency AEs,
though rarely as long or as dramatic as DES. Using the
Yellow Card system in the UK, it was reported that prac-
tolol, a beta-blocker withdrawn from the UK market in
1975, was associated with sclerosing peritonitis, which
did not appear until an average of 201 weeks after the
drug start date (range 0.5–11.5 years).
5
Future for Long-Latency AEs
The US Institute of Medicine addressed long-latency
AEs seen after vaccinations in “Research Strategies for
Assessing Adverse Events Associated with Vaccines: A
Workshop Summary” (1994); however, no particular
new strategy was identified to better find such AEs.
4
Herbst, N Engl J Med 1971; 284; 878–881; Wilcox, N Engl J Med
1995; 332: 1411; Giusti, Ann Intern Med 1995; 122: 778; DES Action
VOICE, Summer 2000 (section adapted from Cobert and Biron,
Pharmacovigilance from A to Z).
5
See Mann RD, Sclerosing peritonitis due to practolol, Pharmacoepi-
demiol Drug Safety 2007; 16(11): 1211–1216.
Acute and Chronic (Late Occurring) Adverse Events, Adverse Events That Disappear 401
The best and only real strategy as of now is to do
long-term follow-up of patients at risk for long-latency
AEs using pharmacoepidemiologic techniques.
Frequently Asked Question
Q: This seems to put the practitioner in an
impossible position. How can one even begin to
make a rational attempt to determine whether
a particular sign, symptom, or AE is due to a
drug (or drugs) taken weeks, months, or even
years ago? The patient may not even remember
or know precisely what he or she was taking.
And how can we even approach AEs due to the
drugs a parent took a generation ago?
A: A valid point. The practitioner really can’t make
such a determination. The finding of very long-term
or skipped-generation AEs remains primarily in the
domain of epidemiology and observational studies.
There is a tendency to run the safety arm of clinical tri-
als for longer periods of time after the acute study is
over. However, even that will not pick up the rare AE
due to the small number of patients involved and the
difficulties of long-term observational studies of safety.
If subjects are followed long enough, all will have AEs
(and will eventually die). That is, there are confound-
ing and coincidental events that make interpretation of
the long-term results very difficult. It may well be that
when large populations have electronic health records,
a more formal health authority-driven-review of large
databases in an ongoing manner will have more sensi-
tivity in discovering long latency, low frequency AEs.
Spontaneous reporting by astute clinicians remains
the best current approach based on the examples seen
to date. Perhaps pharmacoepidemiology and genom-
ics will provide more answers. From the practitioner’s
point of view, a high level of suspicion must be main-
tained. The patient should be quizzed on both recent
and remote drug history, including over-the-counter
medications. Beyond that, we must await better tech-
niques and methodology for tracking drugs taken and
resulting AEs.
It is possible that new techniques coming from AI
will aid in diagnosis of late occurring AEs. But as of now
this is only a hypothesis.
CHAPTER
403
38
Pregnancy and
Lactation
T
esting pregnant animals is done
as part of the usual preclinical
development of new drugs, but
a drug that is not teratogenic (leading
to congenital malformations) in some
or all animal species tested may some-
times, unfortunately, still be noxious
in pregnant women. For increasingly
controversial
1
ethical reasons, clinical
testing is almost never done in preg-
nant women during the development
of new drugs unless the drug is devel-
oped expressly for use in pregnancy.
1
Payne P. Including Pregnant Women in Clinical Research: Practical
Guidance for Institutional Review Boards. Ethics Hum Res. 2019
Nov;41(6):35–40. doi:10.1002/eahr.500036.
Check on the EMA WebSite : “Benefit-risk of medicines used
during pregnancy and breastfeeding”
Thus, the safety and efficacy of drugs in
pregnant women are largely unknown
at the time of marketing, and only a lit-
tle additional information is gained
from spontaneous reporting of adverse
events (AEs).
Introduction
Two tragic stories highlight the risk for the baby when
the mother takes a drug during pregnancy:
Thalidomide: In the early 1960s, thalidomide
was used as an antiemetic to treat morning sickness
in pregnant women. It was found to damage the
development of unborn babies, when taken during
the first weeks of pregnancy. The drug mainly led
to phocomelia (atrophy of the limbs, with the feet
404 Cobert’s Manual of Drug Safety and Pharmacovigilance
and hands implanted directly on the trunk). More
than 10,000 babies were affected around the world,
particularly in Europe.
Diethylstilbestrol (DES): From the 1940s to
the early 1970s, DES was given to pregnant women
because it was thought it would prevent miscar-
riages. In 1971, DES was shown to cause clear cell
carcinoma, a rare vaginal tumor, in girls and women
when they reach puberty who had been exposed
to this drug in utero; recent studies have demon-
strated deleterious effects on granddaughters and
grandsons as well.
These two stories justified the implementation of
more non-clinical testing before marketing and robust
PV systems to warn patients about risks during preg-
nancy. In addition, these new systems were intended to
ensure a rapid and accurate safety signal detection; they
are the cornerstone of the current regulations.
Some drugs are used and, to some degree, tested in
pregnancy, usually in situations in which treatment is
obligatory for either the mother or unborn child (e.g.,
hypertension, asthma, rheumatoid arthritis, epilepsy).
These studies are usually not blinded and are pro-
spective or retrospective observational or surveillance
studies.
Pregnancy registries are now required for manufac-
turers and Marketing Authorization/New Drug Appli-
cation holders for most marketed drugs. That is, every
use of the drug that the company becomes aware of in
a pregnant woman or by a pregnant woman’s partner
is recorded and, with consent, is followed to outcome
(birth, miscarriage, etc.)
Situation in the United
States
According to one report,
2
there are more than six mil-
lion pregnancies in the US each year and 50% of preg-
nant women in the US take at least one prescription
2
Mitchell AA, Gilboa SM, Werler MM, et al., Medication use during
pregnancy, with particular focus on prescription drugs: 1976–2008.
Am J Obstet Gynecol. 2011; 205(1): 51.e1–8.
medicine during pregnancy. Further, use of four or more
medications in the first trimester has tripled (9.9–27.6%)
from 1976 to 2008. Healthcare practitioners and patients
need information on medicines that is relevant for deci-
sion-making during pregnancy (and lactation).
One approach adopted by the US FDA in 1979
was letter categories to “differentiate” products with
data available regarding product use in pregnancy (see
21CFR201; 44FR37434, June 26, 1979, and subsequent
updates). However, these letter categories were not con-
sidered adequate to provide prescribers with enough
relevant information for critical decision-making when
treating pregnant or lactating women.
Thus, a December 2014 final rule (79 Fed Reg
72064; December 4, 2014) required removal of the let-
ter categories from labeling in favor of more complete
statements of known risks, based on the available data
and medical/disease factors, as well as non-clinical data
placed in the context of human data. The final rule
provides an enhanced framework for communicat-
ing information on benefits and risks of using a drug
during pregnancy and lactation to help with prescrib-
ing decisions. The final rule also includes a subsection
on females and males of reproductive potential after or
during attempts at pregnancy.
Before discussing the 2014 final rule, it is of interest
to review the five former letter categories:
Category A: Adequate and well-controlled stud-
ies have failed to demonstrate a risk to the fetus in
the first trimester of pregnancy (and there is no evi-
dence of risk in later trimesters) (see § 201.57(k)
(6){i}).
Category B: Animal reproduction studies have
failed to demonstrate a risk to the fetus and there
are no adequate and well-controlled studies in preg-
nant women (see § 201.57(f)()(ii)).
Category C: Animal reproduction studies have
shown an adverse effect on the fetus and there are
no adequate and well-controlled studies in humans,
but potential benefits may warrant use of the drug
in pregnant women despite potential risks (see §
201.57({)(6)(iii)).
Category D: There is positive evidence of human
fetal risk based on adverse reaction data from
Pregnancy and Lactation 405
investigational or marketing experience or studies
in humans, but potential benefits may warrant use
of the drug in pregnant women despite potential
risks (see § 201.57{](6)(iv)).
Category X: Studies in animals or humans have
demonstrated fetal abnormalities and/or there
is positive evidence of human fetal risk based on
adverse reaction data from investigational or mar-
keting experience, and the risks involved in use
of the drug in pregnant women clearly outweigh
potential benefits (see § 201.57(fl(63(v)).
The letter categories were considered too simplis-
tic and were sometimes misinterpreted as a grading
system. And they did not adequately communicate
risk information for clinical decision-making. Thus,
FDA changed the labeling rules for pregnancy and
lactation and all letter categories were removed by
June 29, 2018. The final rule replaces the letter cat-
egories with three new narrative sections, illustrated
in Figure 1. Note that the affected products have had
the letter categories removed, but elimination of the
standard statements that previously followed the let-
ters was not required.
The A, B, C, D and X risk categories, in use since
1979, are now replaced with narrative sections and sub-
sections to include:
1. Pregnancy (includes Labor and Delivery):
a. Pregnancy Exposure Registry
b. Risk Summary
c. Clinical Considerations
d. Data
2. Lactation (includes Nursing Mothers)
a. Risk Summary
b. Clinical Considerations
c. Data
3. Females and Males of Reproductive Potential
a. Pregnancy Testing
b. Contraception
c. Infertility
Pregnancy
There is now a single subsection (8.1) for “Pregnancy”,
including labor and delivery. If there is a scientifically
acceptable pregnancy exposure registry for the drug,
the “Pregnancy” subsection must contain a specified
statement about the existence of the registry, followed
by contact information needed to enroll or to obtain
information about the registry.
Next is a summary of the risks of using a drug
during pregnancy. If data demonstrate that a drug is not
absorbed systemically, this must be stated. If the drug
is absorbed, risk statements must be included that are
based on data from all relevant sources (whether human
or non-clinical), that describe, for the drug, the risk of
adverse developmental outcomes.
The labeling must also contain relevant informa-
tion, if it is available, to help health care providers make
prescribing decisions and counsel women about the use
of the drug during pregnancy; this could include infor-
mation on disease-associated maternal and/or embryo/
fetal risk, dose adjustments during pregnancy and the
postpartum period, maternal adverse reactions, fetal/
neonatal adverse reactions, and/or the effect of the drug
on labor or delivery.
A good source for further information can be found
at the FDA Office of Women’s Health website.
Also of note is that The FDA and the Substance
Abuse and Mental Health Administration of the US gov-
ernment strongly advise against the use of cannabidiol
(CBD), tetrahydrocannabinol (THC), and marijuana in
any form during pregnancy or while breastfeeding.
Lactation
This subsection (8.2) must contain a summary of the
risks of using a drug during lactation. If data demon-
strate that the drug is not absorbed systemically, there
must be a statement to this effect. If data demonstrate
that the drug is absorbed systemically by the mother,
this summary must include, to the extent it is avail-
able, relevant information on the presence of the drug
in human milk, effects of the drug on a child fed breast
milk, and effects of the drug on milk production. For
drugs absorbed systemically, a risk and benefit state-
ment must appear at the end of the summary of risks,
unless breastfeeding is contraindicated during drug
therapy.
406 Cobert’s Manual of Drug Safety and Pharmacovigilance
The “Lactation” subsection must also include, to
the extent information is available, relevant informa-
tion concerning ways to minimize drug exposure in
the breast-fed child in certain situations, e.g., timing of
dosing relative to feeding. If available, information that
describes available interventions for monitoring or mit-
igating the adverse reactions presented elsewhere in the
labeling.
Females and Males of Reproductive
Potential
The “Females and Males of Reproductive Potential”
subsection (8.3) includes relevant information when
pregnancy testing or contraception is required or rec-
ommended before, during, or after drug therapy or
when there are human or non-clinical data that suggest
the possibility of drug-associated effects on fertility.
The final rule (“Content and Format of Labeling
for Human Prescription Drug and Biological Products;
Requirements for Pregnancy and Lactation Labeling” is
available at https://federalregister.gov/a/2014-28241.
FDA also issued draft guidance to assist manufac-
turers in preparing this section of the labeling (“Preg-
nancy, Lactation, and Reproductive Potential: Labeling
for Human Prescription Drug and Biological Prod-
ucts — Content and Format Guidance for Industry”,
December 2014).
In July 2020 a draft guidance entitled: “Pregnancy,
Lactation, and Reproductive Potential: Labeling for
Human Prescription Drug and Biological Products-
Content and Format” was issued by FDA and should be
reviewed as it is gives detailed information on how the
labeling should be prepared. Although not finalized as
of early 2024, it is, in general, a good idea to follow FDA
draft guidances where this is feasible.
The FDA has also required pregnancy registries to
be maintained by the industry. That is, whenever the
sponsor is aware of a pregnancy it must be recorded
and, with consent, the pregnancy should be followed
to term. These cases are reported in PADERs and/or
PSURs/PBRERs.
FDA Guidance on Pregnancy
Registries — 2002
In August 2002, the FDA issued guidance for industry on
Establishing Pregnancy Exposure Registries. The 2020
draft guidance noted in the previous section should also
be reviewed as it covers pregnancy registries also.
In this guidance, the FDA gives a specific definition
of a birth registry to differentiate it from a teratology
registry:
“A pregnancy exposure registry is a prospec-
tive observational study that actively collects
information on medical product exposure
during pregnancy and associated pregnancy
outcomes.”
This type of registry is not a pregnancy prevention
program.
Note: The FDA did not recommend a registry for all
drugs in this document though now it is expected that
all pregnancies seen during marketing will be followed
to outcome and reported in the periodic reports. These
may not be formal registries as defined in this document
but the data must be tracked and kept:
“We recommend that a pregnancy exposure regis-
try be seriously considered when it is likely that the
medical product will be used during pregnancy as
therapy for a new or chronic condition.”
“A medical product may also be a good candidate
for a pregnancy exposure registry when one of the
following conditions exists:
Inadvertent exposures to the medical product
in pregnancy are or are expected to be common
such as when products have a high likelihood of
use by women of childbearing age.
The medical product presents special circum-
stances, such as the potential for infection of
mother and fetus by administration of live,
attenuated vaccines.”
“Pregnancy exposure registries are unlikely to be
warranted in the following situations: (1) there is
Pregnancy and Lactation 407
no systemic exposure to the medical product, or
(2) the product is not, or rarely, used by women of
childbearing age.”
A registry can be established at any time during the
life of a drug. The applicant or the FDA may initiate
the request. The design of the registry is a function of
the objective. The design may range from an open-ended
surveillance tool to testing of a specific hypothesis.
As of 2023, there were 171 pregnancy registries
being followed by FDA.
Good Epidemiologic Practices
The guidance then details critical elements of a registry,
including objectives, exposure, sample size, eligibility
requirements, data source and content, fetal anomalies
sought, use of an independent data monitoring com-
mittee, an investigational review board, and informed
consent. The reader is referred to the guidance for these
epidemiologic details.
A few points of note from the guidance:
“When estimating the number of exposed
pregnancies to be enrolled prospectively, it
is important to be aware that approximately
62 percent of clinically recognized pregnancies
will result in a live birth, 22 percent will end in
elective termination, and 16 percent will result
in fetal loss (i.e., spontaneous abortions and
fetal death/stillbirth).”
3
Birth defects occur “spontaneously” in a high num-
ber of women. The March of Dimes Birth Defect Foun-
dation, Fact Sheet 2001, reported the following rates for
various pregnancy outcomes and fetal abnormalities:
Spontaneous abortions/miscarriage (loss before
20 weeks): 1 in 7 known pregnancies;
Low birth weight (<2,500 g): 1 in 12 live births;
Fetal death/stillbirth (loss after 20 weeks): 1 in 200
known pregnancies;
3
Ventura, Mosher, Curtin, et al., Vital Health Stat 2000; 21: 56.
Any major birth defect: 1 in 25 live births;
Heart and circulation defects: 1 in 115 live births;
Genital and urinary tract defects: 1 in 135 live
births;
Nervous system and eye defects: 1 in 235 live births;
Club foot: 1 in 735 live births; and
Cleft lip with or without cleft palate: 1 in 930 live
births.
The guidance also notes that other types of stud-
ies, such as case-control studies, may be useful to
evaluate rare adverse birth outcomes and to identify
whether the drug in question is an associated risk
factor. They are useful when long-term follow-up is
needed. They can be nested within other existing preg-
nancy registries.
Automated database studies (e.g., health mainte-
nance organizations, Medicaid) may be useful also.
Regulatory Reporting
Requirements
Registries are considered solicited information and, thus,
must be evaluated and reported as if they were clinical
trial AEs: the cases must be serious, unexpected, and
have a reasonable possibility that the product caused
the AE. See 21CFR310.305(c)(1), 314.80(c)(2)(iii) and
(e), and 600.80(c) (1), (c)(2)(iii) and (e)). Congenital
anomalies are considered serious AEs (21CFR314.80(a)
and 600.80(a)). Registries that are run independently of
applicants holding New Drug Applications are not sub-
ject to post-marketing reporting requirements. How-
ever, such registries frequently supply annual reports to
applicants and, once aware, the NDA holder is subject
to regulatory reporting.
The applicant must also submit an annual status
report to the FDA on any registry being run. A registry
may be discontinued if:
It has accumulated sufficient data to meet the regis-
try objectives;
The feasibility of collecting sufficient informa-
tion diminishes to unacceptable levels due to
408 Cobert’s Manual of Drug Safety and Pharmacovigilance
low exposure, poor enrollment, or unacceptable
loss to follow-up;
Better methods are developed to address the
objectives of the registry;
Termination criteria should be listed in the orig-
inal protocol.
In conclusion, sponsors or applicants who are
studying or marketing drugs that may pose a pregnancy/
teratology threat must give careful and early consider-
ation to adequate data gathering to determine whether
a safety problem exists. If it is already known to exist,
a registry might be established to quantify and track
safety problems. The obvious aim is risk minimization
using the various means available.
See also FDA’s web page on Women’s Health and
pregnancy registries
https://www.fda.gov/ScienceResearch/SpecialTop-
ics/WomensHealthResearch/ucm251314.htm.
Situation in the European Union
Good Vigilance Practice Module VI addresses pregnancy
and lactation (GVP VI, B.6.1). The Marketing Authori-
zation holder (MAH) should follow-up all reports from
healthcare practitioners of drug use in pregnancy; the
same rule applies to consumer reports. If an adverse
event (AE) or an abnormal pregnancy outcome occurs,
this should be an expedited report. This includes con-
genital anomalies, fetal death or spontaneous abortion,
and serious adverse reactions. The health authority
may require exposure data (even without ill effects) for
certain products, such as those with high teratogenic
potential or those where pregnant women would be
exposed. An example of the latter is pregnant women
who are or become infected with HIV.
The MAH is encouraged to collect complete data
and report even normal outcomes in periodic reports, as
this is useful information (reports without an outcome
must be kept but should not be considered as ICSRs).
This is, in effect, a pregnancy registry and such reports
should be included in the PSURs/PBRERs along with
aggregate data on exposure and outcomes. Formal pro-
spective pregnancy registries should also be included.
Further details are available in the European Union
Guideline on the Exposure to Medicinal Products
during Pregnancy. This document notes the issues to
be addressed in Risk Management Plans, data sources,
and types of studies (e.g., case series from spontaneous
reports, record linkage, pregnancy registries, birth-
defect registries, clinical and observational studies, and
non-governmental sources of data). It “aims at provid-
ing criteria to select medicinal products for which active
surveillance for collecting post-authorization data in
pregnancy is necessary. It provides guidance on how to
monitor accidental or intended exposure to medicinal
products during pregnancy and specific requirements
for reporting data and adverse outcomes of pregnancy
exposure. The guideline also includes detailed recom-
mendations regarding presentation of data collected on
exposure in pregnant women.” There is also a discussion
of data quality and data standardization. This excellent
overall review of drugs and pregnancy is worth reading.
Details on Pregnancy Prevention Programs are pro-
vided in the guidance in GVP Module VI (Section B.6.1);
this is applicable to products known or suspected to be
teratogenic.
Labeling in the European Union (the SmPC) should
include the following, as per the 2008 European Union
Guideline (Guideline on risk assessment of medicinal
products on human reproduction and lactation: from
data to labeling):
Clinical data from human experience in pregnancy
with the frequency when appropriate;
Conclusions from developmental studies that are
relevant for assessing risk associated with exposure
during pregnancy. Only malformative, fetotoxic,
and neonatal effects should be mentioned in this
paragraph;
Recommendations on the use of the medicinal
product during the different periods of gesta-
tion, including a sentence on the reasons for these
recommendations;
Recommendations for managing exposure during
pregnancy when appropriate (including relevant
specific monitoring, such as fetal ultrasound and
specific biological or clinical surveillance of the
neonate).
This 2008 guideline includes a table combining
available non-clinical and human data which helps
categorize the risk. A decision tree is also provided to
Pregnancy and Lactation 409
help in prescribing a drug. Finally, standard wording,
depending on the known/available non-clinical and
human data, is proposed for inclusion in the Product
Information.
Lactation
In general, no breast-feeding infant should be exposed
to products the mother takes. In practice, it is not
always feasible for the mother to stop certain critical
drugs. Fortunately, contrary to pregnancy studies, lac-
tation studies are relatively easy to do and can be done
in the study of new drugs; however, robust data on
new drugs are quite limited as very limited studies are
conducted.
Recommendations for Drugs in the 11th WHO
Model List of Essential Drugs”: “There are very few
kinds of treatment during which breastfeeding is abso-
lutely contraindicated. However, there are some drugs
which a mother may need to take which sometimes
cause side effects in the baby.” This publication gives
specifics for many drugs, with specific recommenda-
tions such as “compatible with breastfeeding”, “avoid
if possible”, “avoid breastfeeding”, and “no data avail-
able”. The Sainte Justine Hospital (Canada, Quebec)
has provided robust advice and references for drug use
(article in French) during lactation.
In the European Union, the 2005 guideline about
lactation briefly noted:
If available, clinical data should be mentioned,
including studies on the transfer of the active
substance or its metabolite(s) into human
milk. Information on AEs in nursing neonates
should be included if available. Recommen-
dations should be given to stop or continue
breast-feeding or to stop or continue treatment.
Data on animal studies should be given only if
no human data are available.
Note: The FDA and EMA issued guidances
— FDA: see FDA WebSite: Clinical Lactation Stud-
ies: Considerations for Study Design Guidance
for Industry (2019)
— EMA: see EMA WebSite: Guideline on good
pharmacovigilance practices (GVP) 3 Product-
or Population-Specific Considerations III: Preg-
nant and 4 breastfeeding women (2019)
AEs in Pregnant Partners of Males Taking a Drug
This is an area with little information. Reproductive
studies in animals are done to determine the effects
of new drugs on the testes and sperm. Thus, there are
often animal data in regard to whether a drug is toxic to
the male reproductive system. The major known issues
in this area relate to decreases, often temporary, in fertil-
ity in males. There are few data, however, on toxicity in
the female and the fetus due to transfer of the drug into
the female from the male’s semen or other body fluids.
In general, advice is given to avoid use. This includes
cannabis. An example:
PegIntron and Ribavirin is an antiviral used in com-
bination with interferon-alpha used for treating hepati-
tis C and which should clearly not be used in pregnant
women, women who may become pregnant, and male
partners of women who are pregnant. The FDA-approved
Package Insert notes as follows:
“PegIntron Monotherapy: Pregnancy Category
C: Nonpegylated interferon alfa-2b has been
shown to have abortifacient effects in Macaca
mulatta (rhesus monkeys) at 15 and 30 million
IU/kg (estimated human equivalent of 5 and
10 million IU/kg, based on body surface area
adjustment for a 60-kg adult). PegIntron should
be assumed to also have abortifacient potential.
There are no adequate and well-controlled stud-
ies in pregnant women. PegIntron therapy is to
be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Therefore, PegIntron is recommended for use in
fertile women only when they are using effective
contraception during the treatment period.”
“Use with Ribavirin: Pregnancy Category X: Sig-
nificant teratogenic and/or embryocidal effects
have been demonstrated in all animal species
exposed to ribavirin. REBETOL therapy is con-
traindicated in women who are pregnant and in
the male partners of women who are pregnant
[see Contraindications (4) and the REBETOL
Package Insert].”