Seminars in Fetal & Neonatal Medicine 19 (2014) 264e271

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Seminars in Fetal & Neonatal Medicine

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Review

Assisted reproduction: Ethical and legal issues

Laura Londra 1, Edward Wallach, Yulian Zhao*
Department of Gynecology and Obstetrics at Johns Hopkins University School of Medicine, Division of Reproductive Endocrinology and Infertility,
Lutherville, MD, USA

s u m m a r y
Keywords: Since inception, the use of assisted reproductive technologies (ART) has been accompanied by ethical,
Assisted reproductive technologies legal, and societal controversies. Guidelines have been developed to address many of these concerns;
Biomedical ethics
however, the rapid evolution of ART requires their frequent re-evaluation. We review the literature on
In-vitro fertilization
Legal aspects
ethical and legal aspects of ART, highlighting some of the most visible and challenging topics. Of specific
Reproductive medicine interest are: reporting of ART procedures and outcomes; accessibility to ART procedures; issues related to
fertility preservation, preimplantation genetic testing, gamete and embryo donation, and reproductive
outcomes after embryo transfer. Improvements in ART reporting are needed nationally and worldwide.
Reporting should include outcomes that enable patients to make informed decisions. Improving access to
ART and optimizing long-term reproductive outcomes, while taking into account the legal and ethical
consequences, are challenges that need to be addressed by the entire community of individuals involved
in ART with the assistance of bioethicists, legal counselors, and members of society in general.
© 2014 Elsevier Ltd. All rights reserved.

1. Introduction testing, gamete and embryo donation, and reproductive outcomes

The landscape of reproductive health was forever changed in
1978 after the birth of Louise Brown, ‘the world's first test tube
baby’ [1]. The introduction of in-vitro fertilization (IVF) e with its
ability to segment and modify what in the past had been a rather
obscure biological process e brought as much social, ethical, and
legal controversy as it did happiness and meaning to the lives of
millions of individuals and couples. The basic bioethical principles
of autonomy, beneficence, justice, and avoidance of maleficence are
the pillars with which professional societies within the field of
reproductive medicine have built recommendations guidelines [2].
These principles, although paramount for the protection of all
parties involved, are often difficult to reconcile in the context of
relentless scientific advancement, increasing social demands, and
unique legal frameworks. In this review, we attempt to describe
some of the most visible legal and ethical issues that have arisen in
the dynamic field of assisted reproductive technologies (ART): (1)
the way in which ART reporting systems provide information about
the outcomes of ART procedures; (2) barriers to access to ART
procedures; and (3) the ethical and legal implications of four spe-
cific areas of ART: fertility preservation, preimplantation genetic
* Corresponding author. Address: 10751 Falls Road, Suite 280, Lutherville, MD
21093, USA. Tel.: þ1 410 583 2762; fax: þ1 410 583 2767.
E-mail address: yzhao1@jhmi.edu (Y. Zhao).
1
Edward E. Wallach Fellow in Reproductive Endocrinology and Infertility.
after embryo transfer.
2. Legal and ethical aspects of ART reporting systems
The monitoring of ART practices is essential to improving
infertility care; this includes accurate and thorough reporting of the
procedures and techniques used, as well as the documentation of
reproductive outcomes that result from each type of procedure.
This information constitutes the basis for improving practice
guidelines and policies, and serves as an important resource for
counseling patients.
Worldwide, professional organizations have implemented
reporting systems in order to generate more accurate estimates of
measures of success and outcomes for ART procedures. The fre-
quency and outcomes of techniques that are commonly reported
through these systems include gamete donation, gamete cryo-
preservation, embryo cryopreservation, assisted hatching, and
culture of embryos to the cleavage stage and to the blastocyst stage.
Data on less common procedures such as surrogacy, multifetal
reduction and in-vitro maturation of oocytes are less visible in the
context of worldwide reporting systems. Since 1989, the Interna-
tional Committee for Monitoring Assisted Reproductive Technology
(ICMART; originally known as International Working Group on
Assisted Reproduction) has been reporting on the international
availability, effectiveness and perinatal outcomes, as well as
regional variations, of ART cycles [3]. In the USA, the Fertility Clinic

http://dx.doi.org/10.1016/j.siny.2014.07.003
1744-165X/© 2014 Elsevier Ltd. All rights reserved.
 L. Londra et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 264e271
Success Rate and Certification Act was created in 1992 to stan-
dardize reporting of ART success rates across the country [4]. The
Society for Assisted Reproductive Technology (SART) annually re-
ports data on IVF cycles and birth outcomes for more than 90% of
the ART clinics in the USA. Since 1996, the National Coalition for
Oversight of Assisted Reproductive Technologies (NCOART) has
connected various organizations involved in the practice of ART in
the USA, including the American Society of Reproductive Medicine
(ASRM), RESOLVE (the national infertility advocacy organization for
consumers), the Centers for Disease Control (CDC), the Food and
Drug Administration (FDA), the National Institutes of Health (NIH),
the American Association of Tissue Banks (AATB), the American Bar
Association (ABA), the American Infertility Association (AIA), and
the American Medical Association (AMA) [5]. Starting in 1996, the
CDC initiated data collection on ART procedures performed in the
USA, and since 2004 it has contracted with statistical survey
research organizations to obtain data from IVF clinics through the
web-based National ART Surveillance System (NASS). Relatively
few clinics (~7%) do not report to the CDC and are listed as non-
reporting programs in the Fertility Clinic Success Rates Report.
Because these clinics tend to be smaller and conduct fewer pro-
cedures, NASS is estimated to contain information on more than
97% of all ART cycles performed in the USA [6,7].
Efforts have also been made to link IVF databases with registries
for vital statistics in several states in the USA. Relevant data are
routinely collected at the state level (birth certificate, infant deaths,
hospital discharge, birth defects registries, and cancer registries),
and are being used to conduct state-based surveillance of ART,
infertility and related issues. The goal of this initiative, known as
the SMART Collaborative, is to strengthen the capacity of states to
evaluate perinatal outcomes and programs through state-based
public health surveillance systems [8]. More recently, the Massa-
chusetts Outcomes Study of Assisted Reproductive Technology
(MOSART) database was developed as a similar model to assist in
the understanding of the impact of each step of the IVF process on
particular obstetric and birth outcomes [9].
The ASRM and the ESHRE regularly publish and update guide-
lines for the practice of ART, for techniques that are well estab-
lished, such as IVF and embryo cryopreservation, as well as for
experimental techniques, such as ovarian tissue cryopreservation
[10]. These guidelines rely on the findings of worldwide and na-
tional reports of ART utilization and outcomes, and on scientific
research. As an example, oocyte cryopreservation (OC) is the most
recent technique to evolve from an experimental technique to a
clinically accepted procedure within practice guidelines [11]. It is
now considered reasonable to proceed with OC and banking of
oocytes in women with a medical diagnosis of decreased ovarian
reserve, recurrent fertilization failure, or recurrent failure of em-
bryos to implant, as well as in women for whom embryo cryo-
preservation is not an option (e.g. no partner/sperm donor) [12].
Although the first reported birth after OC occurred in 1986 [13],
technical challenges limited the use of the procedure until recently.
Data from national and international reporting agencies are only
now beginning to accumulate on the long-term outcomes of chil-
dren born after using this technique. Reporting on the outcomes of
IVF using this technique has not produced sufficient data to support
recommendations for its use outside the setting of infertility, i.e. to
ensure the possibility of future pregnancy in healthy women.
3. Legal and ethical issues regarding access to ART
One question that arises frequently regarding infertility treat-
ment access is whether prevention and/or treatment of infertility
are a prudent use of resources [14]. The ‘right to procreate’ can be
viewed as a ‘negative right’ or a ‘positive right’. In the first instance,
265
the state does not interfere with one's ability to reproduce simply
by not mandating sterilization and by not denying the use of
infertility treatments. The case for the ‘positive right’, though, im-
plies that the state should provide resources to help an otherwise
infertile individual to procreate, expanding the concept of ‘access to
the normal range of opportunities in society’ [15] to include the
opportunity to parent a child. The ability to reproduce is considered
the norm in most societies, but the complexity and nuances that
surround the issue of accessibility to reproductive services is re-
flected in the significant policy differences seen worldwide and
even within the USA, where laws and requisites differ from state to
state with regard to access to and extent of insurance coverage for
ART [16].
Recent data on the worldwide prevalence of involuntary child-
lessness indicate that more than 50 million couples would benefit
from a medical intervention to achieve a pregnancy [17]. The con-
sequences of undesired childlessness are particularly acute for
women in developing countries, where unique sociocultural values
are built around procreation, and childlessness often leads to
stigmatization, isolation, ostracism, disinheritance and neglect by
the entire family and community. In such settings, it is not un-
common for entire families to depend on children for economic
survival, which extends the issue of procreation to one of social
welfare and public health [18e20].
In 2004, the World Health Organization proposed ‘the provision
of high-quality services for family-planning, including infertility
services’ as part of its Global Strategy on Diet, Physical Activity and
Health [21]. Yet, some of the most important international non-
profit organizations have continued to limit their focus to safe
motherhood, the reduction of unsafe abortions and prevention of
HIV. In 2006, ESHRE took steps toward providing infertility services
to low-resource countries by forming a Special Task Force on
‘developing countries and infertility’. In 2007, it partnered with The
Walking Egg Project, a non-profit organization that aims to make
infertility care available and accessible through the development of
low-cost ovarian stimulation protocols and simplified culture sys-
tems for IVF [22]. Contrary to common belief, most infertile women
live in underdeveloped nations; The Walking Egg Project aims to
stimulate research on social, cultural, ethical, and legal aspects of
the problem of infertility in these economically disadvantaged
populations [23,24].
4. Ethical and legal implications of ART procedures
4.1. Fertility preservation
The introduction and continuous advances made in the field of
cryopreservation catalyzed the development and application of
fertility preservation techniques for those women, men, and chil-
dren who have a disease or who are undergoing treatment that
threatens their reproductive health. Fertility preservation for pa-
tients with cancer emerged in response to the increasing survival
rates among reproductive-age patients. These patients could
choose to preserve fertile gametes before undergoing gonadotoxic
cancer treatments, with the intention of using them for IVF in the
future [25]. In general, it is recommended that clinicians inform
patients who are about to receive any treatment that could
potentially harm their ultimate ability to conceive regarding the
established methods for fertility preservation. Those methods
include sperm cryopreservation in men and postpubertal boys and
embryo and OC in women and postpubertal girls [26]. Currently,
the cryopreservation of ovarian tissue can only be offered in the
context of a research protocol with institutional review board
oversight [12].
266 L. Londra et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 264e271
Fertility preservation in patients with cancer raises numerous
ethical concerns regarding the welfare of the offspring and the
terms of the informed consent in cases where the individuals do
not survive their cancer or are no longer able to make decisions.
Informed consent in fertility preservation is generally similar to
that used in other situations where gametes or embryos are cry-
opreserved; however, older children and adolescent patients may
also provide assent to undergo fertility preservation procedures
[27]. Following cancer treatment, additional questions require in-
dividual counseling, such as whether it is possible or safe to carry a
pregnancy, which is highly dependent on the type of cancer and
treatment. Fertility options should be reviewed with survivors in
the context of their survivorship status, including trying to conceive
spontaneously if there is remaining gonadal function, using their
cryopreserved gametes or embryos, involving a gestational carrier,
obtaining donated gametes or embryos, seeking adoption services,
or deciding not to pursue pregnancy.
Sperm cryopreservation has been available for decades, but the
introduction of more effective techniques to cryopreserve oocytes,
i.e. vitrification, has raised the possibility also of ‘banking’ oocytes.
Parallels have been drawn between oocyte vitrification and the oral
contraceptive pill in their ability to ‘level the playing field’ for
women who need or want to postpone pregnancy [28]. In 2013,
ASRM officially removed the label ‘experimental’ from OC and
recommended that it be offered to women for fertility preservation
[12]. OC is primarily directed to women or postpubertal girls who
are unable or unwilling to produce embryos for cryopreservation;
for example, young women without a partner or those who are
unwilling to use banked sperm to produce embryos. Some infertile
couples may have failed to obtain sperm on the day of oocyte
retrieval; other patients may have personal or ethical reasons for
not creating embryos at the time of oocyte retrieval. For prepu-
bertal children, the only option for preserving fertility is cryo-
preservation of gonadal tissue. This procedure is still considered
experimental although the number of live births reported after
thawed tissue transplantation continues to increase [29,30].
Beyond its use in patients with cancer, OC is also a reasonable
option for women with BRCA mutations who are advised to un-
dergo salpingo-oophorectomy by age 35 years in order to reduce
the likelihood of ovarian cancer later in life. Conditions associated
with early ovarian failure, such as Turner syndrome and fragile X
syndrome, are additional possible indications for OC. In men, the
most common cause of anticipated loss of gonadal function in a
non-cancer setting is Klinefelter syndrome, which affects one in
600 newborns. Since it is estimated that in 90% of cases these in-
dividuals are going to lose their ability to produce sperm by
adulthood, a recommended strategy is to obtain and cryopreserve
ejaculated sperm from adolescent or adult patients [31,32].
One ongoing ethical issue in the field of fertility preservation
involves pressures to include otherwise healthy women for whom
pregnancy is not possible or desired at the present time. It is
interesting to note that, among IVF practices that offer oocyte
banking, most procedures are not conducted in the context of
infertility or fertility preservation; instead they are elective pro-
cedures designed to cryopreserve gametes for the purpose of
postponing pregnancy for personal or professional reasons, also
known as ‘delayed childbearing’ [33]. ASRM has cautioned prac-
titioners about marketing OC to women, particularly to those in
their late reproductive years for delayed childbearing, as it might
offer false hope with success rates decreasing after age 38 years
[34]. Pregnancy outcomes are also compromised in the older
population, because older women are at increased risk for ob-
stetric complications [35]. For these reasons, there seems to be
insufficient evidence to recommend elective OC for deferred
childbearing [11].
4.2. Preimplantation genetic testing
4.2.1. Preimplantation genetic screening
There is an ongoing quest for methods that can determine
embryo quality and enable the selection of embryos with the
highest potential for a healthy pregnancy and normal baby. Chro-
mosome aneuploidy is a major cause of IVF failure, pregnancy loss
and, rarely, abnormal pregnancy or live birth. Currently, preim-
plantation genetic screening (PGS) enables analysis of the 23 pairs
of chromosomes by comparative genomic hybridization (CGH),
microarray-based CGH (array CGH), digital polymerase chain re-
action (PCR), real-time quantitative PCR, single nucleotide poly-
morphism (SNP) microarray, and next generation sequencing
technologies [36]. PGS therefore is currently used as an adjunct to
IVF to increase pregnancy rates, decrease miscarriage rates and
prevent abnormal pregnancy and live births. Indications for PGS
include advanced maternal age (>35 years), previous aneuploid
pregnancy, repeated IVF failure, repeated miscarriage and severe
male infertility. Because the information provided by PGS will not
change the quality of the embryo cohort, the most useful applica-
tion is to identify aneuploid embryos. Consequently, PGS should
reduce the ‘time to pregnancy’ by increasing the pregnancy rate per
transfer if embryos with the highest implantation potential within
the cohort are transferred first [37]. An additional technical issue
with PGS involves the timing of embryo biopsy during develop-
ment to retrieve cells that are representative of the true ploidy
status of the future offspring. Improvements in implantation rates
and decreases in miscarriage rates have been achieved based on
biopsies of cells at the blastocyst stage of the embryo. Nevertheless,
couples should always be informed about the risk of false-positive
results, which could lead to the discarding of a normal embryo, or
false-negative results, which could lead to the transfer of an
abnormal embryo. Randomized studies that help to establish the
magnitude of these risks for PGS at the blastocyst stage are very
limited; a recent study estimated a clinical error rate of an aneu-
ploidy designation at 4% [38].
The risks associated with embryo biopsy have thus far not been
completely elucidated. Concern centers on damaging a healthy
embryo as a result of the biopsy and on potential long-term effects
in the offspring. Non-invasive methods to assess embryo develop-
ment and quality are thus being developed. Most recently, the
morphokinetic patterns of embryo development in culture, recor-
ded in incubators fitted with time-lapse microscopy, have been
correlated with karyotype results [39]. The effectiveness and ac-
curacy of these technologies for screening embryos is still pre-
liminary, but continue to be pursued because they avoid the
potential risks associated with biopsy.
The ability to analyze the genetic make-up of the embryo prior
to transfer has triggered controversy over the ethical implications
of embryo selection. Concerns exist regarding the consequences of
having genetic information in advance, such as the potential for
gender selection and discarding embryos affected with known
genetic disorders. Gender selection is in itself considered highly
questionable from both ethical and biological points of view. Some
professional organizations have tempered their views when se-
lection is done in the name of ‘family balancing’, i.e. when a family
has only children of the same sex and would like to have a child of
the opposite sex. In their practice guidelines, multiple professional
societies have voiced concerns about the potential for inherent
gender discrimination, inappropriate use of medical resources,
psychological harm to sex-selected offspring (i.e. placing high ex-
pectations on the resulting children), marital conflict over sex se-
lection decisions, and reinforcement of gender bias in society as a
whole [40,41]. The consequences of technologies that enable sex
selection are particularly serious in countries such as India and
 L. Londra et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 264e271
China, where a cultural bias favoring males has led to a severely
altered sex ratio with significantly fewer females [42]. However, an
altered sex ratio in these populations has not been related to the
use of PGS but to the early termination of pregnancies once the sex
of the fetus has been identified [43]. Preconception selection of
gender based on sperm separation or other techniques is still
considered experimental. The ASRM recommends that the use of
ART techniques for ‘family balancing’ should be considered if the
couples are fully informed of the risks of failure, affirm that they
will fully accept children of the undesired sex if the gender selec-
tion technique fails, are counseled about having unrealistic ex-
pectations about the child of the preferred gender, and are offered
the opportunity to participate in research to track and assess the
safety, efficacy and demographics of preconception selection [41].
4.2.2. Preimplantation genetic diagnosis
Preimplantation genetic diagnosis (PGD) was initially developed
to help selected couples prevent the birth of a child with a known
single-gene abnormality or an adult-onset genetic condition. Cou-
ples who wish to have PGD may or may not be infertile; in certain
cases, particularly where one of the parents is a balanced carrier of
a structural chromosome abnormality, infertility or recurrent
miscarriage may be a consequence of the genetic defect. PGD is
considered ethically justifiable when the genetic condition is
serious and there are no known safe, effective interventions to treat
it [44]. The extent to which a condition is considered ‘serious’ is not
clearly defined, but PGD is being used to identify embryos that
carry genes for childhood-onset diseases such as hemophilia or
cystic fibrosis, and, more recently, to identify embryos with single-
gene diseases that do not develop until adulthood, such as Hun-
tington disease, and with cancer predisposition genes such as BRCA
[45]. The use of PGD reduces the chance that parents will be faced
with the difficult decision to terminate a pregnancy if the genetic
disorder is detected during the course of gestation. PGD has been
widely accepted for this purpose, although it has also been sug-
gested that PGD may have the effect of devaluing persons in the
community with disabilities that could have been detected and
selected against in the embryo stage [46]. On the other hand, it has
been reported that, although infrequently, patients who carry
certain genetic conditions such as deafness or dwarfism had
requested PGD on their embryos with the intention of transferring
only those embryos that test positive for the condition, which poses
a very challenging ethical dilemma for the caregiver [47].
The fear that in the future, PGD technology may lead to the
manipulation of genetic material within an embryo is a matter of
concern. The potential for using preimplantational testing to create
a ‘donor child’ who is immunologically compatible with an existing
sick sibling in need of a tissue or organ transplant has raised con-
cerns about the need to set limits for PGD and establish procedures
to protect such children from exploitation until they are able to
make autonomous decisions. In such situations, parents may not be
the best proxy decision-makers, because they face a conflict of in-
terest between their children [46]. Rigorous public and scientific
oversight of these technologies is vital to ensure that scientific
advances are tempered with the best interests of society.
4.3. Gamete and embryo donation
Gamete and embryo donation have significantly expanded the
options available to infertile couples. However, they each pose
unique ethical and legal issues, some of which remain unresolved.
Government and non-governmental agencies, academic in-
stitutions, the public and the media have debated the safety and
well-being of the donors, the infertile couples and, increasingly, the
offspring. Recommendations and guidelines for gamete and
267
embryo donation vary worldwide, reflecting specific needs and
views; the ability to use donor gametes and embryos varies from a
total ban to a lack of specific statutes governing its use [48].
There are at least two aspects of the donation procedure that
highlight the need for regulations, legal agreements, and informed
consent. First, the ability to cryopreserve sperm and oocytes for
later use extends the period of time between the acquisition of the
donated gametes and the actual fertilization and embryo devel-
opment. This temporal separation broadens the potential areas of
ethical and legal contention. Informed consent and legal agree-
ments about the use and storage of the gametes, as well as how
medical records are kept over time, need to include provisions for
periodic updates in the terms of the contract among donors,
practices and recipients.
Another aspect of gamete donation that carries ethical and legal
implications is the fact that oocyte donors must undergo hormonal
stimulation and oocyte retrieval procedures. In comparison to
donation of male gametes, the donation of oocytes introduces a
higher level of medical risk that includes ovarian hyperstimulation
syndrome and surgical complications [49e51]. Although the re-
ported frequency of complications in IVF cycles is relatively low
[52], oocyte donors need to be fully informed of specific risks, and
donation programs have an obligation to ensure that donors have
appropriate health insurance coverage. Additionally, genetic testing
performed in a candidate gamete donor may produce unexpected
information. It is therefore important to have an agreement in place
prior to testing that stipulates how the results and their disclosure
will be managed. Furthermore, whereas donors are asked to be
honest about their family and personal health histories before the
gamete or embryo donation, it is less clear as to what extent donors
should keep programs or recipients updated about relevant health
issues following donation to protect the health of the offspring.
Perhaps two of the most contentious issues surrounding gamete
donation are the disclosure to the offspring and compensation for
donors. Interests and views among involved parties e the donors,
programs, parents and offspring e may vary regarding disclosure of
the use of donor gametes or embryos. Voluntary disclosure is ul-
timately a choice of recipient couples, but, in recent years, the
disclosure to the donor-conceived offspring has been encouraged in
guideline recommendations [53,54]. These recommendations are
supported by studies showing that disclosure may be less disrup-
tive for the donor-conceived person than previously anticipated
[55,56]. Yet, disclosure to the offspring about donor use raises an
additional issue: the right to access information about the donor.
The balancing of the rights of all parties involved requires the
utmost sensitivity [57,58]. Though ASRM has identified different
levels of donor information sharing [59], the most recent recom-
mendations [53], coupled with the concerns voiced by ethics and
legal experts about permitting either the donor or the offspring to
break anonymity, will undoubtedly continue to fuel a lively debate
on this issue worldwide [54,60,61]. In certain countries, such as the
UK, the donor's anonymity can be legally lifted once the child
reaches adulthood, based on the idea that the children were not
part of the original donorerecipient contract and the decision-
making process that motivated their existence. Therefore, the
rights of the children are seen to override those of the adults who
voluntarily participated in the original contract [62]. Furthermore,
the amount of information and record-keeping obligations have
increased, as reflected in recommendations from professional so-
cieties calling for permanent record maintenance [63]. Similar
concerns regarding the management of anonymity issues apply to
the case of embryo donation. Parties must be counseled that even if
proper legal arrangements are in place at the time of the donation
procedure, later changes in law may affect the enforcement of
previous agreements. Another consideration regarding disclosure is
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the possibility that donors may have or plan to have their own
children in the future, such that a donor-conceived child may have
genetic siblings. As such, donors should also be advised that their
present or future partner may have an interest in the consequences
of the donation or its disclosure [58].
The ethical and legal aspects that surround the issue of
compensation for gamete donors has been the subject of intense
media coverage [64,65] and academic debate [60], which has
overwhelmingly focused on the financial incentives for egg do-
nors. The reason is apparent: compared to sperm donors, the
financial compensation for egg donors is far higher, as are the
risks and complexity involved in undergoing an IVF cycle to
retrieve oocytes. The concept of turning human gametes into a
commodity (‘commodification’), has raised ethical concerns and is
given as the main argument against the idea of remunerating
oocyte donors [50]. Regulations governing this practice are
constantly evolving and differ substantially from country to
country. In the USA, the ASRM has affirmed that ‘financial
compensation of women donating oocytes for infertility therapy
… is justified on ethical grounds’ [59,66]. ASRM guidelines state
that ‘time, inconvenience, and discomfort’ associated with the
donation process should be the guide for compensation, rather
than particular human traits, or personal characteristics of the
donors. However, a recent survey found that the content of
34e56% of agency and clinic websites does not reflect the ASRM
recommendations [67] on this matter.
Finally, couples undergoing IVF often reach their desired family
size before transferring all of their generated embryos or using
their cryopreserved gametes. The magnitude of the problem of
unused cryopreserved embryos has been explored in US IVF
practices, under the spotlight of intense media debate regarding
embryo fate [68]. The findings have led to periodic updates on
guidelines from the Ethics Committee of ASRM [69] on the mul-
tiple ways to deal with surplus cryopreserved embryos: thawing
and discarding, donating the embryos to another couple for the
purpose of a pregnancy attempt, donating embryos to an insti-
tution for the purpose of advancing research, and indefinite
storage. Uterine transfer of the embryos at a time not favorable to
implantation has been proposed as a sensible way of dealing with
the fate of these embryos [70]. One area of recent debate has been
the use of surplus embryos for stem cell research, which overlaps
with the issue of donating oocytes for research [71e73]. Each of
these strategies has encountered supporters and detractors
[71,74,75], which ultimately reflects in the wide variations in laws
and regulations in place worldwide. At present, US law does not
give clear guidance on discarding abandoned embryos. The ASRM
continuously provides updated guidelines on how best to manage
these issues in a rapidly changing scientific and legal environment
[69,71,76e79].
4.4. Reproductive outcomes after ART
ART is associated with potential risks to both the mother and
fetus. Because multiple embryos are transferred in the majority of
ART procedures, ART has been associated with a substantial risk for
multiple-gestation pregnancy and multiple births [6,80,81]. Mul-
tiple births are associated with greater health problems for mothers
and infants, including higher rates of caesarean deliveries, prema-
turity, low birth weight, infant death, elevated risk of birth defects
and disability [82,83]. The contribution of ART to adverse perinatal
outcomes in recent years is mainly due to the persistently high
number of twin pregnancies. The transfer of a single embryo in
patients with a favorable prognosis has been shown to be effective
in keeping pregnancy rates and live birth rates high, but with a
significant reduction in multiple births; however, the ethical forces
at play in the absence of a mandatory policy or oversight regarding
the number of embryos transferred have been difficult to reconcile
in the USA [2]. In Europe, the Belgian model of practice with single-
embryo transfer (SET) is an example of a successful intervention.
From 1 July 2003, SET and elective SET have been established by
Belgian law in first and second IVF cycles, respectively, for patients
aged <36 years [28].
Interestingly, even singleton infants conceived with ART have a
higher risk of low birth weight [84e86], and data suggest that
micromanipulation procedures such as intracytoplasmic sperm
injection may be associated with an increased risk of congenital
anomalies [87]. Extended embryo culture, which was initially
introduced as a way to naturally select the single healthiest and
most viable embryo for transfer, thereby decreasing multiple
pregnancy rates, has not yet fulfilled this goal. Conversely, the
culture of embryos up to day 5 of development has been associated
with a greater incidence of perinatal morbidity when conception
has occurred after a fresh embryo transfer [88e90]. The question
remains as to whether suboptimal pregnancy outcomes are related
to the underlying infertility of the couples, whether they are
associated with intrinsic effects from certain IVF procedures, such
as hormonal stimulation, embryo culture media, micromanipula-
tion techniques, or whether they are due to a combination of pa-
tient and procedure effects [88,91,92].
Although the vast majority of babies born after IVF are found
to be healthy, efforts should be made to continue to document
short- and long-term health outcomes of the offspring and to
accurately inform and update couples on the results of this sur-
veillance [93]. Additionally, some studies have suggested that
infants of IVF pregnancies may be at a small but statistically
significant increased risk for rare epigenetic abnormalities [94].
Because the first IVF procedure was performed as recently as
1978, true long-term data do not yet exist. With time and diligent
patient follow-up, it will be possible to accurately evaluate health
outcomes and adverse effects of ART, such as effects on fertility
potential or the risk of malignancies later in life in individuals
conceived through IVF.
5. Conclusions
While giving hope to millions of infertile couples, ART has
presented new ethical, legal, and social questions that society as
a whole must address. Many countries have taken steps to
regulate certain aspects of ART, but regulations and ethical dis-
cussions have historically been slower than medical progress.
Society must reconcile how to fund ART in a responsible and
equitable manner to increase access to care. Looking ahead,
preimplantation genetic testing promises to alter the current
capabilities of ART, but this will likely come with a host of new
legal and ethical questions and controversies. It is imperative that
ART practitioners continue to pursue and lead the investigations
and debate over adverse reproductive outcomes related to the
use of these technologies, in order to ensure that ART services are
offered and delivered in a manner that achieves optimal patient
care while taking into account the social and moral re-
sponsibilities raised by these procedures and their downstream
consequences.
 L. Londra et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 264e271 269

Practice points

 The accuracy and completeness of national and international reporting systems in ART practice are essential to the improve-
ment of infertility care worldwide.
 The creation of databases that link ART reports of procedures with birth reports is critical to benchmark treatment of infertility
and perinatal outcomes, as well as short- and long-term outcomes after the use of ART.
 Identity disclosure to the offspring and compensation to donors are the most visible issues in gamete and embryo donation. The
debate is an ongoing one and there is a wide range of policies and guidelines worldwide.
 Preimplantation genetic testing can help couples avoid the transfer of an embryo affected by a known childhood or adult-onset
genetic disease. Nevertheless, counseling on the decision to use these techniques in couples with no specific indication of an
increased risk for genetic conditions should take into account the scarcity of randomized studies and long-term outcome data on
these pregnancies.
 The continuous surveillance of reproductive outcomes after the use of ART is an ongoing quest as new techniques are brought
into practice at a very dynamic pace. Because the first ART procedures took place only three decades ago, long-term outcomes
data are limited. Therefore, couples should be informed of reported risks of adverse outcomes in order to be able to make
informed decisions regarding the extent of the use of ART procedures.

Research directions

 The role of ART reporting systems in understanding the impact of the IVF process on perinatal and long-term outcomes of the
offspring.
 The socio-economic consequences of undesired childlessness for women in underdeveloped countries.
 The role of health insurance coverage in the access to infertility care in developed countries.
 The role of providers in offering fertility preservation techniques to both female and male patients who are about to undergo
treatments that can decrease their ability to procreate in the future.
 The safety and effectiveness of gonadal tissue cryopreservation for fertility preservation in prepubertal individuals.
 The effects of long-term gamete and embryo cryopreservation on donors, recipients and offspring and its ethical and legal
implications for each of them and for the maintenance of records by infertility care providers.
 The biological and social consequences of ‘delayed childbearing’ and the role of ART in the care of women with a desire to
preserve their reproductive potential.
 Randomized studies that help establish the false-positive and false-negative rates of results from preimplantation genetic testing
of embryos, as well as the cost-effectiveness of extending the use of these techniques to patients with no indication of being at
increased risk of aneuploidy or known genetic disorders.

Conflict of interest statement
None declared.
Funding sources
None declared.
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