Addressing the Growing
Problem of Multiple Gestations
Created by Assisted Reproductive Therapies
Gary S. Nakhuda, MD, and Mark V. Sauer, MD
Iatrogenic multiple pregnancy is the most significant complication of assisted reproductive
technology (ART). Approximately half of all children born subsequent to ART result from a
plural gestation. Furthermore, the majority of triplets and higher order births are the product
of ART. The risks for multiple pregnancy vary with practice patterns and the techniques
used to achieve pregnancy. Recognizing the potential for serious morbidity associated with
multiple pregnancies, infertility specialists have developed strategies to reduce the complication of multiple pregnancies while maintaining acceptable pregnancy rates. Implementation of these refined practices has led to a reduction in the incidence of higher order
multiple births, although the incidence of twins has yet to be minimized. Further reduction
in the incidence of multiple births after ART necessitates a redefinition of success to
emphasize the healthy singleton birth rate, rather than crude pregnancy rates.
Semin Perinatol 29:355-362 © 2005 Elsevier Inc. All rights reserved.
KEYWORDS IVF, multiple gestation, twins
A
healthy child delivered at term is the ideal endpoint of
treatment for an infertile patient. Despite the general
acknowledgment of this standard of success and the universal recognition that multiple gestations, compared with singletons, are associated with increased maternal and perinatal
complications, current standards of care favor the risk of
multiple pregnancies over the risk of failure to conceive. The
acceptance of such risks focuses practices on maximizing
pregnancy rates at the expense of increasing the incidence of
iatrogenic multiples. Twins and higher order births have accounted for as much as 56% and 12.8%, respectively, of all
births resulting from assisted reproductive technology
(ART).1 The contribution of ART to higher order births has
been estimated to range from 50% to 80%.2,3 Over a 20-year
period from 1980 to 1999, the absolute incidence in higher
order multiple pregnancies increased from 37.0 to 193.5
births per 100,000 live births, an increase of 423%,4 with the
largest increase in proportion of multiple pregnancies coinciding with the regions reporting the greatest number of ART
procedures.1,4 From 1980 to 1997, 20% of triplets and higher
order births were attributed to spontaneous events, 40% to in
Division of Reproductive Endocrinology and Infertility, College of Physicians & Surgeons, Columbia University, New York, NY.
Address reprint requests to Gary Nakhuda, MD, 622 West 168th Street, Dept
OB/GYN, PH16, New York, NY 10032. E-mail: gsn16@columbia.edu
0146-0005/05/$-see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2005.08.003
vitro fertilization (IVF) and related procedures, and 40% to
ovulation induction.5
Given the personal and societal costs associated with the
complications of multiple births, practice patterns of reproductive endocrinologists have public health implications.
Techniques to reduce or eliminate the incidence of iatrogenic
multiple conception may dramatically impact on the number
of complications related to plural gestation. Although such
techniques have been suggested, efforts to implement them
into practice have met resistance. The reputation and popular
opinion of infertility centers are commonly derived from the
“bottom-line” pregnancy rates. Conservative approaches that
favor singleton births are characterized by lower per cycle
success, and possibly decreased overall success secondary to
drop-out from treatment, a result of patient stress and frustration at the prolonged time to conception.6,7 Patients’ desires to achieve pregnancy in a timely fashion, and the perception of twins as a desirable outcome8 further contributes
to the pervasive use of aggressive practices that predispose to
multiple gestation.
In recent years, practice patterns are integrating approaches that carry less risk for multiples. In 1999, there was
a decline in the overall ratios for higher order multiple birth,
reversing the increasing trend observed since the 1980s.4 In
2002, over 90% of 375 board-certified reproductive endocrinologists responding to a survey stated that they believed it
355
356
was worthwhile to risk decreasing their overall pregnancy
rate for the purpose of reducing the incidence of higher order
pregnancy.9 Although multifetal pregnancy reduction is an
effective method of reducing the incidence of higher order
multiples, it is not an acceptable option for all patients and is
not without risks.10,11 The goal of assisted reproduction
should include prevention of multiple conception, rather
than simple reliance on a secondary intervention. This review
summarizes the fertility treatments that predispose to multiple pregnancies and the current efforts to reduce the risks
while maintaining acceptable birth rates.
Ovulation Induction
Ovulation inducing agents are the staple of modern assisted
reproduction. Ovulation induction (OI) is the practice of
stimulating mono-ovulation in anovulatory patients, whereas
controlled ovarian hyperstimulation (COH), also known as
superovulation, refers to the stimulation of multi-follicular
development. Whenever more than one follicle is stimulated
to maturity, there is a theoretical risk of multiple gestation.
When insemination occurs in vivo subsequent to polyovulation, it is impossible to control the number of oocytes that
will fertilize or the number of preembryos that will implant.
Hence, the use of ovulation inducing medications is a major
risk for multiple gestation. Gonadotropin stimulation is the
main cause of higher order multiple gestation in the United
States and Europe.12-16 Depending on the indication, various
ovulation inducing strategies exist with variable risks for
multiple gestation.
Clomiphene citrate (CC) has been in clinical use in the
United States since 1967. It is a standard first line therapy in
normo-gonadotropic anovulatory patients (WHO group II),
of whom up to 70% will ovulate on standard doses. CC is also
used for COH in normo-ovulatory patients, with or without
intrauterine insemination (IUI). CC is safe, inexpensive, easy
to use, and without major side effects for most patients. The
rate of twins after CC is on the order of 5% to 10%, and the
rate of triplets or higher order pregnancy is less than 1%.17
For ideal candidates, the pregnancy rate per cycle with CC
(8% with IUI and 5.8% without IUI) is significantly lower
than injectable gonadotropin OI.18,19 Nonetheless, 20% of
patients will fail to ovulate on CC, necessitating the use of
another OI agent. Although CC may not be as effective as
gonadotropins, it remains an option for properly selected
patients for achieving pregnancy with a significant but relatively lower risk for multiple births.
In the case of CC resistance, alternative treatment options
are available for certain subgroups of patients before resorting to gonadotropin therapy. For patients with polycystic
ovarian syndrome (PCOS), metformin can be used with or
without CC and is useful for inducing ovulation in patients
who are resistant to CC alone. In a recent meta-analysis,
metformin was effective in achieving ovulation in women
with PCOS, with an odds ratios of 3.88 for metformin compared with placebo and 4.41 for metformin and CC compared with CC alone.20 Given the beneficial metabolic effects
of metformin, in addition to the ovulation inducing action,
G.S. Nakhuda and M.V. Sauer
metformin is considered by many as first line therapy for
some patients with PCOS. Another option for patients with
PCOS is ovarian drilling with laparoscopic diathermy, the
modern version of the traditional wedge resection, originally
reported to be effective in inducing ovulation in up to 95% of
PCOS patients.21 Although the procedure is invasive and is
associated with the inherent risks of laparoscopy, compared
with gonadotropins, it may be as effective in achieving live
birth with reduced overall cost and without the risks of ovarian hyperstimulation and multiple pregnancy.22 However,
evidence suggests that metformin may be more efficacious in
achieving overall reproductive outcomes than laparoscopic
drilling, thus the surgical approach should be reserved for
cases of failed medical intervention.23 Third generation aromatase inhibitors (AIs) have recently emerged as useful single
agents for ovulation induction as an alternative to CC, for CC
resistant patients, and as adjuncts to gonadotropin stimulation.24 Preliminary studies have demonstrated higher pregnancy rates with significantly reduced multiple pregnancy
rates compared with CC.25,26 AIs are promising agents for OI
with an apparently reduced risk for multiple pregnancies
compared with conventional treatments. However, large
scale prospective studies have yet to be published. While it is
desirable to avoid the risks of gonadotropins, the clinician
must recognize that a certain subset of patients will not be
amenable to CC and the alternative therapies. Exhausting the
alternative strategies simply to avoid the risks of gonadotropins may not be in the best interest of the patient.
Controlled Ovarian
Hyperstimulation with Gonadotropins
Treatment with gonadotropins is an effective means of
achieving pregnancy in a heterogeneous group of infertile
patients, which includes those with hypogonadotropic hypogonadism (WHO I), clomiphene resistance, unexplained infertility, and couples with mild to moderate male factor infertility when combined with IUI. Purified urinary gonadotropins
and/or recombinant FSH are used largely interchangeably. Gonadotropins are expensive, require parenteral administration, and are associated with significant risks for OHSS. Most
significantly, gonadotropins are associated with a high risk of
higher order multiple pregnancy. A large prospective multicenter trial designed to compare the efficacy of IUI or intracervical insemination (ICI), with or without gonadotropins,
for couples with unexplained infertility, found the highest
pregnancy rate (33% per couple) when COH was performed
in conjunction with IUI.27 In the study, of 86 pregnancies
that resulted in live births subsequent to gonadotropin superovulation, 24 were multiple gestations, including 17 sets
of twins, 4 sets of triplets, and 3 sets of quadruplets. In
another large study designed to assess the risk factors associated with multiple pregnancies after COH, of 441 intrauterine pregnancies, 88 (20%) were twins, 22 (5%) were triplets,
10 (2.3%) were quadruplets, 5 (1.1%) were quintuplets, and
2 (0.5%) were sextuplets.13 The authors confirmed the previously recognized association of young age, peak estradiol,
and number of follicles with the risk of multiple pregnancies,
ART and multiple gestation
but concluded that more effective criteria to identify patients
at risk could not be developed without compromising overall
pregnancy rates. Given the unacceptably high rates of high
order multiple pregnancies subsequent to gonadotropins, the
authors challenged the justification for the continued use of
the practice when a lower risk, more effective option [in vitro
fertilization (IVF)] is available.13
Despite acknowledgment of the high risks of COH with
gonadotropins, it is still a useful technique for properly selected patients. Though more expensive than oral therapies,
the direct costs of treatment with gonadotropin COH are
more affordable than IVF and thus may be more accessible
for some patients. Compared with COH-IUI, IVF is associated with additional practical and theoretical risks, including
a surgical procedure requiring anesthesia and the ex vivo
handling of gametes and embryos. Patients with personal,
religious, or moral objections to the in vitro creation and
destruction of embryos may find COH-IUI to be a more acceptable option. For these patients, the focus is on identification of risks factors to minimize the complication of multiple pregnancies while still offering a reasonable probability
of success.
Several methods for reducing the risks for multiple gestations after COH with gonadotropins have been proposed.
The most common of these is cycle cancellation. When the
patient appears to be at risk, gonadotropins are discontinued,
hCG is withheld, and the patient is instructed to refrain from
intercourse. After a variable rest period, the patient may attempt stimulation again, presumably on a lower dose of medication. Although effective in preventing multiple pregnancy,
cycle cancellation is rather disappointing to patients and physicians, who invest considerably in the procedure, only to
have that cycle “wasted” with no immediate possibility of
pregnancy. Furthermore, making the decision to cancel a
cycle is difficult, due to a lack of universal criteria for cancellation. The traditional indicators of impending risk for multiple pregnancies are (1) serum estradiol and (2) number
and/or size of the maturing follicles. Estradiol is secreted
from the granulosa cells of the growing follicle, with a mature
value believed to be 200 to 300 pg/mL per follicle. As a
harbinger for multiple pregnancies, the cut-off value is controversial, ranging from 800 to 3000 pg/mL at the time of
hCG administration.13,14,27,28 Lower values of peak estradiol
are believed to be associated with a lower incidence of multiple pregnancies, although no published study has prospectively compared these cut-offs with their respect to effect on
multiple pregnancy. Similarly, the threshold value of follicular size and number is debatable. Some authors stress the
importance of considering all follicles as a risk for multiple
pregnancy, whereas others only consider the number of large
follicles to be a predisposing condition.29 Unfortunately, no
consensus on optimal criteria for minimizing multiple pregnancies while maintaining acceptable pregnancy rates has
been reached, most likely because of the heterogeneity of the
patient populations treated with gonadotropins. Until definitive evidence appears, vigilant monitoring of COH cycles,
with liberal, individualized cancellation policies based on
357
experienced clinical judgment is necessary if the risk of multiple pregnancies is to be minimized.30
To avoid excess stimulation that may lead to cycle cancellation, several authors have proposed “gentle” ovarian hyperstimulation to induce the development of fewer follicles.
These protocols typically involve lower empiric starting
doses of gonadotropin with gradual, low incremental increases until adequate follicular responses are achieved. Alternatively to such “step-up” protocols, others advocate
“step-down” protocols, where the gonadotropin dose is reduced after the initial follicular recruitment phase. In a series
of low fixed dose or step-up protocols, pregnancy rates
ranged from 9% to 37%, with multiple pregnancies rates
ranging from 0% to 29%.31 Curiously, the study with the
highest pregnancy rate of nearly 37% (13/63 cycles) also
boasted a 0% incidence of multiple pregnancies.32 This protocol was unique in employing the addition of a GnRH antagonist to prevent a premature LH surge and had more stringent criteria for cancellation (⬎2 follicles ⬎15 mm).
Additional studies are needed to validate these promising
findings.
Another proposed method for reducing the risks for multiple pregnancies when excessive follicular development ensues is the conversion of the COH cycle to an IVF cycle.
Conversion to IVF may be more satisfactory to the patient, as
it allows for the chance of pregnancy with the current cycle,
whereas cancellation offers no hope for pregnancy until the
following cycle. Excellent pregnancy rates have been reported with this technique, however, the risk for multiple
pregnancies remains significant.33,34 Conversion to IVF substantially adds to the costs of the cycle and thus may not be
feasible for all patients. However, for patients who are informed of the risks and costs of the procedure, conversion to
IVF may be an attractive alternative to cycle cancellation.
One additional strategy that has been proposed for minimization of risks of multiple conceptions after gonadotropin
stimulation is the aspiration of supernumerary follicles before ovulation.35,36 The objective is to reduce the number
of oocytes available for fertilization while leaving an appropriate number in situ to maintain a chance for pregnancy.
Like conversion to IVF, this technique allows the salvage of
an overzealous COH cycle. It also requires additional expense and a minor procedure, which may not be acceptable
to all patients. However, it appears to be a viable technique
that may be useful for some patients.
Despite best practices, the physician must be aware that
the risk for multiple pregnancies after gonadotropin stimulation remains high and may be unpredictable. In contrast to
IVF data, which is tracked with a national registry, the impact
of COH on the epidemic of multiple births can only be estimated due to a lack of a similar registry. No precise criteria
are available as clear predictors of multiple gestation, hence
formal practice guidelines for COH are lacking.37 However, a
general risk profile for a patient at risk can certainly be appreciated: a young patient with a high serum estradiol and
multiple follicles. The patient should only proceed with COH
after full disclosure of not only the incidence of multiple
gestations, but the potential for maternal and perinatal com-
358
plications. Only physicians with specialized training and experience should prescribe gonadotropins.
In Vitro Fertilization
In 2001, 107,587 cycles of IVF and related procedures (ie,
IVF-ICSI, GIFT, ZIFT) were reported to the CDC through the
Society for Assisted Reproductive Technology (SART) database.38 Of the 40,687 newborns born subsequent to these
procedures, 53% were from multiple births, of which 46%
were twins and the remainder were triplets and greater. The
multiple pregnancy rates were even higher than the live birth
rates, since many of the plural pregnancies were reduced,
either spontaneously or by intervention. Although IVF procedures accounted for 1% of the national birthrate, multiple
pregnancies from these procedures alone accounted for 16%
of all multiple pregnancies that year. Fortunately, it is becoming evident that physicians may be able to largely correct the
problem by adopting new practice patterns that can reduce
the incidence of iatrogenic multiples without significantly
compromising pregnancy rates.
In IVF cycles, at least three factors are related to the risk of
multiple births: age, implantation rate, and the number of
embryos transferred. Age of the patient (in nondonor cycles)
is inversely related to the probability of multiple pregnancies,
as it is for overall pregnancy success. Implantation rate is
determined by numerous variables, but perhaps most importantly by the embryo quality. Finally, the number of embryos
transferred is directly proportional to the risk of multiple
pregnancies, and for any given patient, the most controllable
of these variables.
Age
In the case of spontaneous twin conception, advanced maternal age appears to be a relative risk factor even as fecundity
decreases.39 With assisted reproduction, age is inversely correlated to live birth rate when nondonor eggs are used. In
2002, only 12.6% of 40-year-olds, and 4% of patients older
than 42 achieved live birth after IVF, compared with 37% of
patients younger than 35.40 Although the age of the patient
obviously cannot be manipulated, use of a young oocyte donor substantially improves the pregnancy rates for patients
with diminished or depleted ovarian reserve. The use of a
young donor (one in her 20s or early 30s) confers a live birth
rate of approximately 50% per transfer across all age groups
of recipients. In 2002, 13,183 donor oocyte cycles were performed in the U.S., and the vast majority occurred in women
over the age of 39.40 Of the 4195 pregnancies that occurred
subsequent to donor egg cycles that resulted in live birth,
more than 42% produced more than 1 infant.40 Therefore,
although ART has improved the probability of live birth in an
older patient, the most successful technique (donor egg) puts
the patient at significant risk for multiple pregnancies.
Improving Implantation
Implantation rate is defined by the probability that a given
preembryo will initiate a pregnancy after being transferred.
Many factors may influence the potential to implant, includ-
G.S. Nakhuda and M.V. Sauer
ing the quality of the oocyte and embryo, the receptivity of
the uterine environment, and the skill of the physician performing the transfer. However, the major focus in improving
the implantation rate has been on selecting the preembryo
with the greatest potential for continued development in
utero. The most widely advocated means for improving the
selection process is blastocyst culture. Extending in vitro culture to 5 days to reach the blastocyst stage, as opposed to the
typical 2 or 3 days performed for cleavage stage embryos,
offers several purported advantages. Whereas embryo development after 2 days is governed by presynthesized maternal
transcripts, extending culture to 5 days allows for postembryonic genomic activation and thus more accurately demonstrates the embryo’s capacity for continued development.41 Additionally, extension of the culture period allows
for a synchronization of the uterine environment with the
preembryo, as physiological implantation occurs closer to the
blastocyst stage rather than the early cleavage stage.42 Initial
attempts at blastocyst transfer were unsatisfactory, with pregnancy rates of 7% despite 40% of embryos surviving in culture to day 5, demonstrating that simply prolonged survival
in culture does not predict continued survival in utero.43
With newer developments in culture systems, initially with
coculture techniques44 which were eventually superseded by
the use of sequential media,45 dramatic improvements in implantation rates were reported. Overall implantation and
pregnancy rates in nonselected patients have been reported
to be significantly higher with day 5 transfer (61.6% implantation, 46.9% pregnancy) versus day 3 transfer (47.5%,
36.9%).46 Critics of blastocyst transfer argue that fewer patients will have embryos that will survive to day 5, thus increasing the rate of cycle cancellation. Although studies have
demonstrated a higher cancellation rate after retrieval than
with day 3 culture, those studies have also reported increased
pregnancy rates per retrieval when blastocyst culture was
performed.46,47 Initially, poor blastocyst survival after cryopreservation was another argument for favoring cleavage
stage transfer, as day 3 embryos fared better after cryopreservation than day 5 embryos, offering patients additional transfer attempts per ovarian stimulation cycle.48 However, subsequent improvements in technique have led to efficient
postthawing survival and pregnancy rates, making cryopreservation of blastocysts a viable option.49 Unfortunately,
whereas a large body of evidence promotes blastocyst culture
as a means for improving implantation rates, a recent Cochrane review of randomized trials that compared the effectiveness of blastocyst versus early cleavage stage transfer did
not determine a clear advantage of blastocyst culture.50 No
evidence of overall improved pregnancy or birth rates or
decreased multiple pregnancy rates was demonstrated,
whereas blastocyst cycles had a higher cancellation rate and
fewer available embryos for cryopreservation. However, the
subset of trials employing sequential media did demonstrate
higher implantation rates per embryo, suggesting that improvements in culture techniques may lead to conditions that
allow for the efficient transfer of fewer embryos. In 2002,
75% of all transfers were performed on day 3; however,
across all age groups, live birth rates were higher when blas-
ART and multiple gestation
tocyst transfer was performed.40 Unfortunately, cycle cancellation and multiple pregnancy rates for the subset of blastocyst transfers are not available.
Preimplantation genetic diagnosis (PGD), the chromosomal analysis of blastomeres biopsied from cultured embryos, has been suggested as another method for improving
implantation rates. PGD has traditionally been used for gender selection (for medical or social purposes), for sibling HLA
matching, and for detecting aneuploidy or single gene disorders. Its use for selecting patients as a means for improving
implantation is controversial.51 Although implantation may
improve in some subsets of patients,52 as a means for reducing the incidence of multiple pregnancies, PGD will likely
have little impact, as the incidences of implantation failure
and multiple gestation are inversely correlated.
The Number of Embryos Transferred
It has long been recognized that the incidence of higher order
multiple pregnancies after IVF is a complication that could be
minimized by reducing the number of embryos transferred.53-56 To this end, in 1998 the American Society of
Reproductive Medicine (ASRM) published initial guidelines
for the number of embryos to transfer.57 According to these
guidelines, patients with “above average” prognosis (less than
35 years old), “average” prognosis (35-40 years old), and
“below average” prognosis (older than 40, or those who have
failed several previous cycles), should have a maximum of 3,
4, or 5 embryos transferred. In the years following the publication of these guidelines, the mean number of embryos
transferred decreased, as did the rate of triplet and higher
order multiple pregnancies reported to the CDC registry,
whereas the rate of twins remained relatively constant.58,59 In
an effort to further reduce the incidence of multiples, including the rates of twins, ASRM published refined guidelines for
the transfer of cleavage stage embryos in 2004.60 According
to the updated criteria, patients with the “most favorable”
prognosis, including patients under 35 years old, those having their first cycle of IVF with good quality embryos and
excess quantity for cryopreservation, and patients with previous successful IVF attempts, should have a maximum of 2
embryos transferred “in the absence of extraordinary circumstances.” Additionally, for patients in the age range of 35 to
37 years, with a “more favorable” prognosis, no more than 2
embryos were recommended for transfer. For patients with a
history of 2 or more failed IVF cycles and for those with a “less
favorable” prognosis, no limit was placed on the number of
embryos to transfer. No discrete recommendations were
made for blastocyst transfer, but it was suggested that fewer
embryos be transferred at the blastocyst stage. In 2002, 62%
of nondonor transfers involved 3 or more embryos, 28%
involved 4 or more, and 10% involved 5 or more. The highest
live birth rates (39.5%) occurred in patients who received 2
embryos. In patients who received more than 2 embryos, the
live birth rates did not increase, whereas the triplet or greater
rate increased to between 5% and 6%, compared with 0.7%
when 2 embryos were transferred. In all cases where 2 or
359
more embryos were transferred, the incidence of twin births
was approximately 32%.40
Although the reduction in the incidence of higher order
multiple pregnancies is a promising trend, the persistence of
an unacceptable twinning rate deserves more attention.
Twins have a four-fold increased probability of neonatal
death61 and present well-established risks for obstetric and
neonatal complications and long-term disability.62,63 Furthermore, twins born after IVF may be at even greater risk for
adverse outcome than those that are spontaneously conceived.64 Even in countries that legally restrict the maximal
number of embryos transferred to 2 or 3, the incidence of
twins, at 20% to 35%, remains significant.65,66 Recognizing
that current practices have not curbed the avoidable complication of twin gestation, much attention has recently been
paid to the option of single embryo transfer (SET), which
would all but eliminate iatrogenic multiple pregnancies, with
the exception of monozygotic twinning. Although the benefit
of SET in terms of reducing the complications associated with
multiple pregnancies is evident, apprehension exists concerning the potentially considerable reduction in birth rates,
thus the practice has yet to be widely embraced.
The concept of SET was first proposed in 198867 with
more recent reports coming from Europe since 1999.68,69
These studies emphasized that, even though the pregnancy
rates were lower with SET compared with double embryo
transfer (DET), SET still resulted in acceptable success rates
(29.7-38.5%) with the benefit of preventing multiple pregnancies (0-10%). A recent study from Gardner and coworkers compared single versus double blastocyst transfer, reporting no statistical difference in the high ongoing pregnancy
rates in both groups (60.9% and 76%, respectively), with no
twins in the single transfer group compared with a nearly
50% incidence in twins when 2 blastocysts were transferred.70 Although the data were encouraging, the number of
patients undergoing SET was small in each trial. A large multicenter trial comparing SET to DET was reported in 2004 by
Thurin and coworkers.71 Two approaches were compared for
their ability to achieve live birth and avoid multiple pregnancies: (1) transfer of 2 fresh embryos, versus (2) transfer of a
single fresh embryo, followed by a transfer of a single cryopreserved embryo if the initial fresh attempt was unsuccessful. Forty-three percent of 331 patients who had DET
achieved live birth, 33% of whom had multiple births. In the
SET group of 330 patients, nearly 28% of patients achieved
live birth after fresh transfer, with an additional 16% having
a baby after the thawed embryo cycle, for a cumulative live
birth rate of almost 39% (95% CI 33.3-44.5). Only one twin
pregnancy occurred in the SET group. Although the two
methods did not achieve equivalence by the standards set by
the authors, the 95% confidence intervals demonstrated that
the plausible difference in birth rate between the SET and
DET would not be more than 11.6 percentage points. Given
the conspicuous reduction in multiple pregnancies and the
insubstantial difference in birth rates, the authors concluded
that SET is a viable method for maintaining IVF success while
dramatically reducing the risk for multiple births. In all studies, for patients to be considered for SET, they had to be in the
G.S. Nakhuda and M.V. Sauer
360
best prognostic category, ie, less than 35 or 36 years of age
with high quality embryos. It remains to be seen if SET offers
other prognostic groups a reasonable chance of live birth.
However, with nearly half of all women in the U.S. who
undergo IVF meeting these favorable criteria,38 application of
Thurin’s technique in this group alone could markedly reduce the iatrogenic multiple birth rate. In the U.S. in 2002,
only 6.7% of all transfers involved only 1 embryo, with a live
birth rate of 12.8%, with a 2% twin rate. In women younger
than 35 with extra embryos available for future transfer, the
live birth rate with SET was 47.4%, 100% of which were
singletons. Using the live singleton birthrate as the measure
of success, the highest rate is seen in the case of SET.40
Conclusions
The majority of adverse outcomes in children conceived with
IVF are related to multiple gestation.72,73 Given that the problem of multiple pregnancies after assisted reproduction is
well recognized and potential solutions are available, the issue becomes how to effect change. In several countries, the
maximum number of embryos permitted for transfer is dictated by legislation. Violation of these laws may result in
severe penalties to the physicians performing the procedures,
ranging from fines, to revocation of medical license, to imprisonment.74,75 The most restrictive policy appeared in Sweden in 2003, where the National Board of Health and Welfare
decreed that all transfers should be limited to a single embryo, except in patients for whom the risk of twinning is
considered to be low.76 Although legislation may prove effective in enforcing practices which reduce the incidence of
multiple pregnancies, in a country such as the United States
where personal liberties are highly valued, legal intervention
would likely be unwelcome by patients and physicians alike,
and could unnecessarily politicize the ability to make autonomous reproductive choices.77 Furthermore, the limitations
placed by legal restraints may not consider the best therapeutic options for all groups of patients.
Efforts should focus on the factors that perpetuate the
permissive attitude of accepting unnecessary risks. Recent
efforts have been made to redefine “success” after ART. Min
and coworkers suggested reporting IVF outcomes based on
“birth emphasizing the successful singleton at term
(BESST).”78 The authors argued that presenting this statistic
as a ratio of all initiated cycles would signify an important
philosophical change, recognizing that a healthy singleton
pregnancy is the ultimate goal of assisted reproduction. Patients must be educated on the reality of multiple pregnancy.
Even if a multiple pregnancy concludes without complication, the stress and practical difficulties associated in raising
children from multiple births is significant, possibly requiring psychiatric treatment even in families with adequate material resources.79,80 In addition, the short-term financial incentive to become pregnant quickly should be removed.
When patients have to pay for each intervention, it is predictable that they would want to maximize the probability of
pregnancy on the first cycle. The remarkable disparities in
costs of care between raising singletons and multiples may
not be appreciated by a couple that may be immediately faced
with a bill for thousands of dollars for each fertility procedure. In states where insurance coverage defrayed the costs of
IVF, the mean number of embryos transferred and the percentage of triplet or higher order pregnancies was lower than
in those without mandated coverage.81 Finally, the phenomenon that Howard Jones refers to as “inductor isolation”
needs to be addressed: while fertility specialists are the inductors of the multiple pregnancy problem, they are isolated
from the consequences.59 If the self-serving isolation continues, the problem will certainly not improve, and external
intervention, most likely in the form of legislation, may be
necessary. Hopefully, a combination of these ideological
changes along with improvements in the medical care of
infertile patients will eventually foster a standard of care
where multiple pregnancies will be regarded as an anomaly
rather than a consistent complication.
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