18.3 Research Involving Pregnant Women,
Human Fetuses and Neonates
18.3.1 Definitions
Dead fetus - a fetus that exhibits neither heartbeat, spontaneous respiratory activity,
spontaneous movement of voluntary muscles, nor pulsation of the umbilical cord.
Delivery - complete separation of the fetus from the woman by expulsion or extraction
or any other means.
Fetus - the product of conception from implantation until delivery.
Neonate means a newborn. A newborn is considered a neonate up to 30 days of
age. A newborn, 31 days old will be considered a child for research purposes.
Nonviable neonate - a neonate after delivery that, although living, is not viable.
Pregnancy encompasses the period of time from implantation until delivery. A woman
is assumed to be pregnant if she exhibits any of the pertinent presumptive signs of
pregnancy, such as missed menses, until the results of a pregnancy test are negative or
until delivery.
Viable, as it pertains to the neonate, means being able, after delivery, to survive
(given the benefit of available medical therapy) to the point of independently
maintaining heartbeat and respiration.
Stillborn death or stillbirth means death prior to the complete expulsion or extraction
from its mother of a product of human conception, occurring after the twentieth week
of pregnancy and does not include “induced termination of pregnancy. Colorado
Revised Statutes, §25-2-102(4.5).
Induced termination of pregnancy means the purposeful interruption of a pregnancy
with the intention other than producing a live-born infant or removing a dead fetus that
does not result in a live birth. Colorado revised statutes, §25-2- 102(2.7).
18.3.2
Research Involving Pregnant Women or Fetuses
Research that involves pregnant women and fetuses can only occur if all of the
following conditions are met (45 CFR 46.204):
When appropriate, preclinical studies including studies on pregnant animals
and clinical studies, including studies on non-pregnant women, have been
conducted and provide data for assessing the potential risks to pregnant
women and fetuses;


The risk to the fetus is caused solely by interventions or procedures
that hold out the potential of direct benefit for the woman or the fetus,
or
If there is no potential of benefit, the risk to the fetus must be minimal,
and;
The purpose of the research is the development of important
biomedical knowledge which cannot be obtained by any other means.
Any risk is the least possible for achieving the objectives of the research. No
inducements, monetary or otherwise, may be offered to terminate a pregnancy.
Researchers may not take part in decisions as to the timing, method, or
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procedures used to terminate a pregnancy.
Members of the research team may not determine the viability of a neonate.
18.3.2.1 Who Can Consent
The mother may consent for the study if:
The research holds out the potential of direct benefit to the pregnant
woman, or both the pregnant woman and fetus, or;
If there is no benefit for the woman or fetus and the risk to the fetus
is minimal, and;
The purpose of the research is the development of important
biomedical knowledge that cannot be obtained by any other means.
The mother and father must consent for the study if:
The research holds out the potential of direct benefit solely to the fetus,
The father’s consent need not be obtained if he is unable to
consent because of unavailability, incompetence or temporary
incapacity or the pregnancy resulted from rape or incest.
COMIRB requests that you document the reasons for not obtaining the father’s
consent in your files.
Each individual providing consent must be fully informed regarding the reasonably
foreseeable risks of the research on the fetus or neonate.
Any minor parent can give permission for their child to participate in research but the
parent/guardian of the minor parent must give permission for the minor parent to
participate in the research. Parental permission is not required if the minor parent is
emancipated as defined by Colorado State Law.
18.3.2.2 VA Regulations
 Research in which the subject is a fetus, in-utero or ex-utero (including
human fetal tissue) must not be conducted by VA investigators while on
official duty, or at VA facilities, or at approved off-site facilities.
 Research related to in vitro fertilization must not be conducted by VA
investigators while on official duty, or at VA facilities, or at approved offsite facilities.
18.3.3
Research Involving Neonates
Neonatal research is dependent on the viability status of the neonate (45
CFR46.205).
A neonate that is viable may participate in research only to the extent outlined by 45
CFR 46 subparts A and D.
Neonates whose viability is not certain may participate in research if COMIRB
determines that the research:
Holds out the prospect of enhancing the survival of the neonate to the
point of viability and the risk is minimized for achieving that goal,
or
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The development of important biomedical knowledge which cannot be
obtained by other means,
and
There can be no added risk to the neonate from the research.
In addition:





The appropriate preclinical and clinical studies have been carried out
that allow for adequate risk assessment.
A neonatologist or pediatrician not associated with the research
determines the viability of the neonate.
Informed consent of either parent of the neonate is obtained
If neither parent is able to consent because of unavailability,
incompetence, or temporary incapacity, the legally authorized
representative [LAR] of either parent may provide informed consent.
COMIRB requests that you document the reasons for why you
obtained the legally authorized representative’s consent.
The consent of the father is not needed if the pregnancy resulted from
rape or incest.
After delivery, nonviable neonates may be involved in research only if the following
conditions are met:





The vital functions of the neonate are not artificially maintained
The research will not terminate the heartbeat or respiration of the
neonate There are no additional research risks to the neonate
The purpose of the research is the development of important
biomedical knowledge that cannot be obtained by other means
Informed consent of either parent of the neonate is obtained
If neither parent is able to consent because of unavailability,
incompetence, or temporary incapacity, the legally authorized
representative of either parent may provide informed consent.
COMIRB requests that you document the reasons why you obtained
the legally authorized representative’s consent. The consent of the
father is not needed if the pregnancy resulted from rape or incest
18.3.4
Research Involving After Delivery: The Placenta or
Dead Fetus or Fetal Material
Research involving the placenta following delivery; the dead fetus, macerated fetal
material; or cells, tissue, or organs removed from the dead fetus shall follow the
appropriate federal, state or local laws and regulations (45 CFR 46.206).
If the above tissue’s information is recorded so that living individuals can be
identified, then the living individuals are considered research subjects. Informed
consent must be obtained from the living individuals.
No physician or institution that performs procedures for the induced termination of
pregnancy shall transfer such tissue for valuable consideration to any
organization or person that conduct research using fetal tissue or that transplants fetal
tissue for therapeutic purposes. (Colorado revised statutes, §25-2-111.5). [Valuable
consideration means simply any profit or gain.]
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18.3.5
Research not Otherwise Approvable
For research not funded by DHHS, if the COMIRB finds that the research presents a
reasonable opportunity to further the understanding, prevention, or alleviation of a
serious problem affecting the health or welfare of pregnant women, fetuses or
neonates; and the research is not approvable under the above provisions, then the
COMIRB will consult with a panel of experts in pertinent disciplines (for example:
science, medicine, ethics, law). Based on the recommendation of the panel, the
COMIRB may approve the research based on either:
a. That the research in fact satisfies the conditions above, as applicable; or
b. The following:
The research presents a reasonable opportunity to further the
understanding, prevention, or alleviation of a serious problem
affecting the health or welfare of pregnant women, fetuses or
neonates;
The research will be conducted in accord with sound ethical principles; and
Informed consent will be obtained in accord with the provisions for
informed consent and other applicable sections of this manual.
DHHS-funded research that falls in this category must be approved by the Secretary
of Health and Human Services. If the COMIRB finds that the research presents a
reasonable opportunity to further the understanding, prevention, or alleviation of a
serious problem affecting the health or welfare of pregnant women, fetuses or
neonates; and the research is not approvable under the above provisions, then the
research will be sent to OHRP for DHHS review.
Summary of Policy on Pregnant Women in Research
1) COMIRB policy identifies prospective collection of data involving pregnant women, or
regarding pregnancy course and outcomes, as research involving pregnant
women/fetuses. By federal regulations, collection of research data involving or regarding a
pregnant woman/fetus during a study is considered research involving pregnant women. A
further question arises when subsequent data collection is desired regarding an inadvertent
pregnancy to provide safety information about a test article. This specific type of data collection
also meets both the Common Rule and FDA definitions of research. COMIRB therefore
considers all such activity as research. For studies in which a pregnancy was inadvertent,
subsequent follow-up should be thought of by investigators as a sub-study involving pregnant
women.
2) For the purposes of reviewing a study for including pregnant women, COMIRB policy
differentiates between studies based on enrollment intent of pregnant women and the
likelihood of pregnancy during the trial. The materials required for studies performing
research involving pregnant women, and the timing of COMIRB review of these materials, will
depend on the enrollment intent and the likelihood of pregnancy during the trial. Please see the
decision tree to determine the category of a study.
a) Studies in which pregnant women are not excluded, and studies in which pregnancy
is likely to occur (no attempt is made to avoid/prevent pregnancy), will be considered by
COMIRB as enrolling pregnant women if any research activity with pregnant women is planned
(categories A and B). Such studies require review for inclusion of pregnant women at the time
of initial review.
b) Studies that exclude pregnant women from enrolling and take measures to avoid
pregnancy during the trial will be considered initially by COMIRB as studies that do not enroll
pregnant women, even if research activities are planned for women who inadvertently become
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pregnant during the trial (category C). Such studies should report pregnancy during the trial as
an unanticipated problem and then submit the required documents for review at the time of a
pregnancy.
With regard to studies involving investigational drugs, COMIRB recognizes the guidance
of the FDA International Conference on Harmonization; Guidance on General Considerations
for Clinical Trials, section 3.1.4.3. (a) “In general, pregnant women should be excluded from
clinical trials where the drug is not intended for use in pregnancy. If a patient becomes pregnant
during administration of the drug, treatment should generally be discontinued if this can be done
safely. Follow-up evaluation of the pregnancy, fetus, and child is very important. Similarly, for
clinical trials that include pregnant women because the medicinal product is intended for use
during pregnancy, follow-up evaluation of the pregnancy, fetus, and child is very important.”
Due to the importance of clinical safety follow-up of inadvertent fetal exposures to test
articles during research activities, COMIRB policy is designed to present the minimum allowable
barriers to this type of follow-up. Such safety follow-up of unintended cases is important to
provide special medical knowledge that currently cannot be obtained by any other means. The
follow-up information must be provided to both the Sponsor of the trial and the FDA to aid in the
detection of potential toxicities when evaluated in aggregate with other exposure data.
COMIRB Policy on Pregnant Women in Research: Categories A – C
A. Pregnant women are enrolled into (not excluded from) the study.
The following are required for initial COMIRB review:
i)
Attachment J.
ii)
Consent form must have language specific to pregnant women/fetuses.
iii) Risks to pregnant women and fetus must be disclosed in the consent.
iv) If information is to be collected about the neonate (birth to 30 days of age), the
COMIRB application must include Attachment I.
v)
If information is to be collected about the child from the pregnancy beyond 30
days from the time of birth, the COMIRB application must also indicate the
inclusion of children as a vulnerable population (and Attachment H included).
vi) Note: If data on fetuses, neonates, and/or children is to be collected, the
offspring is considered a human subject. Enrollment numbers reported to
COMIRB must reflect the enrollment of this subject, and the consent form must
describe the procedures and risks to the fetus/neonate/child. If the VAMC is a
study site, contact the VA research office to determine whether a CRADO waiver
is required.
B. Pregnant women are excluded from enrollment, but at least one pregnancy is
anticipated, or no measures are taken to avoid/prevent pregnancy during the trial.
A woman who becomes pregnant during the study will undergo some or all research
procedures (pregnant women are retained [enrolled] in research), even if safety
follow-up procedures only are planned. COMIRB would recognize the study as
enrolling pregnant women because pregnancy prevention is not attempted, unless
COMIRB determines that pregnancy is not likely to occur. The following are required for
initial COMIRB review:
i)
Attachment J.
ii)
Anticipated risks to pregnancy/fetus of exposure to research intervention must be
disclosed in consent.
iii) If study procedures are identical for pregnant/non-pregnant women, consent
must state whether the research intervention will be stopped, and that the woman
may elect to continue with remaining study procedures in the event of pregnancy.
iv) If study procedures will be altered for women who become pregnant, Attachment
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v)
vi)
vii)
J must describe the procedures pregnant women will undergo and separate
consent/HIPAA B forms for pregnant women are required.
If information is to be collected about the neonate (birth to 30 days of age), the
COMIRB application must include Attachment I.
If information is to be collected about the child from the pregnancy beyond 30
days from the time of birth, the COMIRB application must also indicate the
inclusion of children as a vulnerable population (and Attachment H included).
Note: If data on fetuses, neonates, and/or children is to be collected, the
offspring is considered a human subject. Enrollment numbers reported to
COMIRB must reflect the enrollment of this subject, and the consent form must
describe the procedures and risks to the fetus/neonate/child. If the VAMC is a
study site, contact the VA research office to determine whether a CRADO waiver
is required.
C. Pregnant women are excluded from the study and efforts exist to prevent pregnancy
during the trial (counseling on avoiding pregnancy in the consent form or as part of
standard of care for the study population, or subjects are required to use birth control
during the study).
If a woman incidentally becomes pregnant during the study, she would be asked to
continue some or all research procedures (COMIRB would not recognize the study as
enrolling pregnant women unless a pregnancy occurs). The following are the minimum
required for initial COMIRB review:
i)
The following language in the Application (under Data Safety Monitoring Plan):
“This study excludes women who are pregnant and counsels subjects on the
prevention of pregnancy during the trial. Any pregnancy that inadvertently occurs
in a study subject or a partner of a subject will be reported to COMIRB as an
unanticipated problem. In the case of an unintended pregnancy, continued
follow-up is desired and we will submit the required documents for review per
COMIRB's policy on pregnant women in research, section C."
ii)
Appropriate language in the consent counseling subjects against becoming
pregnant and/or requiring use of birth control.
iii) A statement in the consent that if the subject becomes pregnant, the research
intervention will (or will not) be stopped, the subject will be given the option to
continue with research assessments, and she will be asked to sign a separate
consent if this occurs.
If a pregnancy subsequently occurs during the study the following materials are required
for COMIRB review.*
i)
Attachment J.
ii)
If study procedures are identical for pregnant/non-pregnant women, the original
consent must state whether the research intervention will be stopped, and that
the woman may elect to continue with study procedures in the event of
pregnancy.
iii) If study procedures will be altered for women who become pregnant, Attachment
J must describe the procedures pregnant women will undergo and a separate
HIPAA B form for pregnant women is required.
iv) If study procedures will be altered for women who become pregnant, and all
subsequent procedures pose minimal risk to the woman and offspring, a
consent form is not required.†
v)
If information is to be collected about the neonate (birth to 30 days of age), the
COMIRB application must include Attachment I.
vi) If information is to be collected about the child from the pregnancy beyond 30
days from the time of birth, the COMIRB application must also indicate the
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vii)
inclusion of children as a vulnerable population (and Attachment H included).
Note: If data on fetuses, neonates, and/or children is to be collected, the
offspring is considered a human subject. Enrollment numbers reported to
COMIRB must reflect the enrollment of this subject, and the consent process
must disclose the procedures and risks to the fetus/neonate/child. If the VAMC is
a study site, contact the VA research office to determine whether a CRADO
waiver is required.
*
When these materials are submitted to COMIRB at the time of a pregnancy, the PAM/UPD will
be approvable on an expedited basis by the Chair, provided the proposed research activities
involving pregnant women are determined to be minimal risk and meet the criteria for expedited
approval of research. Though COMIRB recommends submitting these documents only once an
unanticipated pregnancy occurs, they can be submitted at any time for review, including at the
time of initial review, if desired.
†
COMIRB recognizes that many pregnancy sub-studies are intended for clinical safety follow-up
and will pose only minimal risk to the subject and offspring. In these situations, it will be
COMIRB policy to waive the requirement for documentation of informed consent as permitted
under 45 CFR 46.117(c)(2) and 21 CFR 56.109(c)(1). A verbal consent process between the
investigators and the subject is required. At the Chair’s or convened IRB’s discretion,
documentation of informed consent can be required even if subsequent procedures meet the
criteria for minimal risk research.
Additional consideration: research on the pregnant partner of a research subject
If information is to be collected from a study subject’s partner who becomes pregnant while the
subject is enrolled, the study should be categorized identically as it would for the pregnancy of a
female subject of the trial (category A, B, or C above). The partner (and the offspring, if
applicable) must be enrolled as a research subject and documents must be submitted for review
according to the instructions under the appropriate category above. HIPAA A is required for the
investigators to contact the partner directly; alternatively, a recruitment plan requesting the
subject to have the partner contact the investigators is acceptable. The pregnancy consent
form (if applicable) must be written to be inclusive of pregnant partners.
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