CONTROVERSY Twin pregnancy, contrary to consensus, is a desirable outcome in infertility

ARTICLE IN PRESS
CONTROVERSY
Twin pregnancy, contrary to consensus, is a desirable
outcome in infertility
Norbert Gleicher, M.D.,a,b,c and David Barad, M.D., M.S.a,b,d
a
The Center for Human Reproduction, New York; b Foundation for Reproductive Medicine, New York, New York; c Department
of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut; and
d
Departments of Epidemiology and Social Medicine and Obstetrics, Gynecology and Women’s Health, Albert Einstein
College of Medicine, Bronx, New York
Objective: To determine whether the worldwide consensus that twin pregnancy after fertility treatment represents
an adverse outcome to be avoided is correct.
Design: Literature search via PubMed and MEDLINE, going back to 1990.
Setting: Academically affiliated private fertility center.
Patient(s): Mothers and offspring in singleton and twin pregnancies.
Intervention(s): None.
Main Outcome Measure(s): Maternal and perinatal/neonatal risks as well as cost considerations for singleton
versus twin pregnancies.
Result(s): Most risk assessments of twin pregnancies after fertility treatment have used spontaneous conceptions
data, which reflect different treatment paradigms and outcome benefits from pregnancies after fertility treatments.
In vitro fertilization (IVF) twins demonstrate approximately 40% lower outcome risks than spontaneous twin
conceptions. Most risk assessments in the literature are calculated with pregnancy as the primary outcome, but
in a fertility-treatment paradigm where patients want more than one child the statistically correct risk assessment
should refer to born children as the primary reference. If published data are corrected accordingly to achieve
statistical commonality of outcome (i.e., one child in singleton versus two children in twins), twin pregnancies
no longer demonstrate a significantly increased risk profile and/or cost for mothers or individual offspring.
Conclusion(s): For infertile patients who want more than one child, twin deliveries represent a favorable and costeffective treatment outcome that should be encouraged, in contrast to the current medical consensus. (Fertil Steril
2008;-:-–-. 2008 by American Society for Reproductive Medicine.)
Key Words: Twins, twin pregnancy, multiple births, in vitro fertilization, infertility, fertility treatment, adverse
outcomes
In recent years, multiple births have skyrocketed, with most
of the increase attributable to infertility treatment (1–3).
Because multiple pregnancies increase the risk to mothers
and offspring, this development has caused worldwide concern (4, 5). Risks, of course, further increase as the order of
multiples rises (6, 7). Thus, initial efforts have concentrated
on reducing high order multiples when the potential of risk
is the greatest (5, 8, 9). More recently, however, aggressive
worldwide efforts have turned toward reducing the prevalence
of twin pregnancies because they represent a large majority of
Received January 29, 2008; revised and accepted February 26, 2008.
N.G. has nothing to disclose. D.B. has nothing to disclose.
Supported by the Center for Human Reproduction, New York and the
Foundation for Reproductive Medicine.
Presented in part by invitation in form of a debate (Twins in ART Is a Desirable Outcome?) at the 14th World Congress on In Vitro Fertilization
and 3rd World Congress on In Vitro Maturation, Montreal, Canada,
September 15–19, 2007.
Reprint requests: Norbert Gleicher, M.D., The CHR 21 East 69th Street,
New York, NY 10021 (FAX: 212-994 4499; E-mail: [email protected]
com).
0015-0282/08/$34.00
doi:10.1016/j.fertnstert.2008.02.160
multiple births after fertility therapy (10, 11). These efforts,
originally initiated mostly by European investigators, have
resulted in the concept of single-embryo transfer for in vitro
fertilization (IVF), which has achieved wide popularity and
has been aggressively communicated to the public (12–15).
A principal argument in favor of reducing twin pregnancies
has been medicine’s primary ethical charge to do no harm.
Because singletons are widely assumed to be safer than
twin deliveries, the argument has been that fertility treatments
should (even at the possible expense of reducing pregnancy
chance) mount every possible effort to avoid the added risks
of twins. This argument is, however, flawed and should, therefore, no longer be conveyed to the public. As this article will
demonstrate, for most infertility patients, single-embryo transfer strategies are inappropriate.
MATERIALS AND METHODS
Using MEDLINE and PubMed, we performed a literature
search retroactive to 1990 that addressed risk and cost
Fertility and Sterility Vol. -, No. -, - 2008
Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
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ARTICLE IN PRESS
comparisons between singleton and twin deliveries. The following key words were used: twins, twin pregnancies, twinning, multiple births, infertility, infertility treatment, in vitro
fertilization (IVF), assisted reproductive technologies (ART),
single embryo transfer, perinatal mortality, perinatal morbidity, maternal mortality, maternal morbidity, prematurity,
pregnancy complications, cost, and cost effectiveness.
Historical Perspective
Most multiple births after fertility treatments are not a consequence of IVF but of other fertility therapies (3, 8). Indeed,
IVF represents the only fertility treatment that offers a reasonable degree of control over the multiple pregnancy risk by
allowing the number of embryos transferred into the uterus
to be determined (8). This recognition led to the concept of
age-specific and ovarian function–specific embryo transfer
criteria in attempts to control the risk of multiple births
with IVF (16).
The logic of such criteria seemed obvious when twoembryo transfer (2-ET) was demonstrated to achieve identical pregnancy rates to the higher-order transfer numbers in
properly selected women (17, 18). Once outcomes were comparable, there was no longer an indication to even consider
procedures with potentially higher risk profiles. However,
outcome were not identical when single-embryo transfer subsequently was compared with 2-ET and was found to result in
lower pregnancy rates (though, of course, also significantly
lower twinning) (19–21).
In view of an allegedly higher risk profile of twin pregnancies, proponents of single-embryo transfer nevertheless
argued that lower risk profiles for singleton pregnancies
made lower pregnancy rates acceptable; diminished pregnancy potential can, after all, be made up with more interventions (i.e., more embryo transfers or more IVF cycles). They
overlooked, however, that with single-embryos transfer any
established pregnancy will, in principle, always be a singleton
pregnancy, resulting in birth of one child, whereas every twin
pregnancies gives birth to two children. To equalize outcomes
by number of children (and not by pregnancy), every woman
who initially managed to deliver a singleton will have to undergo a second (singleton) pregnancy experience.
Risk/Benefit
Because risk/benefit evaluations represent the basis of all
medical practice, they also should apply to infertility patients.
The principal desired benefit from fertility treatment is relatively simple to define: it is not clinical pregnancy but rather
the birth of (healthy) children. Indeed, it is usually not just the
birth of a single child because a majority of women want
more than one child. Specific data on this topic are mostly
lacking, but it is possible to extrapolate from related data
sets: over two thirds, for example, prefer twins over singletons if given the choice, and a surprising minority even wants
triplets (22). Such a conclusion also was supported by two recent nonscientific Internet polls (23, 24), which concluded
2
Gleicher and Barad
Twin pregnancy after IVF
that only 11% of 140,000 and 6% of 18,000 respondents
wanted a single child.
Number of desired children represents a very important
consideration in determining the risk/benefit of fertility therapy accurately. If a hypothetical couple initiates fertility
treatment with the goal of having two (or more) children,
their maximal potential benefit from treatment would, of
course, be the delivery of two (healthy) children in as short
a time frame as possible (and, as we shall further discuss,
at the lowest possible cost). Their risks (and costs) are then
rather simple to assess as defined by the cumulative risks
(and costs) of all pregnancies/deliveries (and treatments)
required to deliver two children. In other words, if this hypothetical couple had two children as the result of a single twin
pregnancy, their risks (and costs) would be those of this one
twin pregnancy. If, however, two singleton pregnancies were
required to deliver two children, their overall risks (and costs)
would be defined by the cumulative risks (and costs) of those
two pregnancies.
The correct statistical conclusion from all of this is, therefore, that an outright comparison of risk (and cost) between
a singleton and a twin pregnancy, with pregnancy as the
reference point, is for infertility patients (in contrast to obstetric patients) nonsensical. A corrected statistical comparison
requires the acknowledgment that after a singleton delivery
a woman (who wants at least two offspring) will need further
infertility treatments (though even such treatment can never
guarantee a successful second pregnancy) and at least one additional pregnancy (baring miscarriages) to reach the desired
outcome of two delivered children. Any second singleton
pregnancy will then double the singleton risks (and costs)
of her first pregnancy without guaranteeing a second successful delivery.
Mathematically, this means that, if the risk for one offspring in a singleton pregnancy is x, the combined risk for
two offspring in two singleton pregnancies will be 2x. The
principal question that now arises is whether this 2x risk
does or does not exceed the risk of one twin delivery.
Of course, this model somewhat oversimplifies: it assumes
that outcomes are statistically independent, which in obstetrics is rarely the case (e.g., maternal age will affect practically
every outcome parameter), and it primarily reflects nonidentical twin pregnancies, which obviously are the relevant ones
when the number of embryos to be transferred in IVF is the
subject of dispute.
That risks diverge if assessed per offspring versus per pregnancy is well recognized in reproductive medicine and is
widely applied in genetic counseling of couples with multiple
pregnancies before prenatal genetic diagnosis (25). Thus,
why this knowledge has not been properly used in comparing
risk/benefits of singletons and twins after fertility therapies is
somewhat puzzling. Excluding the rare infertility patient who
only wants one child, the uncorrected comparison of risk
factors between singleton and twin pregnancies, as has
been the practice in the literature, appears inappropriate.
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Risk Comparisons
The medical literature is abundant in demonstrating
increased maternal (26) and perinatal/neonatal (6, 7, 27–35)
risks for twins in comparison with singleton pregnancies.
However, most studies were based on spontaneous conceptions and not on pregnancies after infertility and/or IVF
treatments. Van Wely et al. (36) summarized some of these
data, based on recent European Society for Reproductive
Medicine (ESHRE) data (37) and a national Danish data set
(Table 1) (38–40).
Probably the most thorough analysis was presented by
Helmerhorst et al. (28), who compared the outcome of singletons and twins with an exclusive concentration on assisted
conception cycles. Reviewing 25 published studies on the
subject (17 studies with and 8 without matched controls),
these investigators concluded that singleton pregnancies after
TABLE 1
Adverse outcomes with twins delivered.
Study
Maternal
Sibai et al., 2000 (31)a
Hypertension
Preeclampsia
MacKay et al., 2006 (26)
Maternal mortality
Perinatal/neonatal
Fitzsimmons et al., 1998 (27)
Perinatal mortality/1000b
Helmerhorst et al., 2004 (28)a
Very preterm
Preterm
Very low birth weight
Low birth weight
Small for gestational age
Cesarean section
Neonatal ICU
Perinatal mortality/1000
Van Wely et al., 2006 (36)a
Preeclampsia
Eclampsia
Placental abruption
Postpartum hemorrhage
Anemia
Pinborg et al., 2004 (40)a
Birthweight <2500 gram
Birthweight <1500 gram
Gestational age 32—37 weeks
Gestational age <32 weeks
Stillborn
Neonatal death within 7 days
Neonatal death within 1 year
Major birth defects
Minor birth defects
Patent ductus arteriosus
Spontaneous twins
2.0 (1.6–2.6)
2.6 (2.0–3.4)
IVF twins
Corrected (L40%)
—
—
1.4 (1.0–1.6)
1.6 (1.2–2.0)
20.8 (vs 5.7; x 3.6)
—
24
—
—
—
—
—
—
—
—
—
0.95 (0.78–1.15)
1.07 (1.02–1.13)
0.89 (0.74–1.07)
1.03 (0.99–1.08)
1.27 (0.97–1.65)
1.21 (1.11–1.37)
1.05 (1.01–1.09)
0.58 (0.44–0.77)
3.7 (3.3–4.3)
3.4 (1.2–9.4)
2.0 (1.2–3.3)
3.4 (2.9–4.1)
1.7 (1.5–1.9)
—
—
—
—
—
12.5 (x 2.2)
2
2.2 (2.0–2.6)
2.0 (0.7–5.6)
1.2 (0.7–2.0)
2.0 (1.7–2.5)
1.0 (0.9–1.1)
7.1 (6.3–8.0)
5.0 (3.9–6.5)
5.9 (5.2–6.6)
5.0 (3.9–6.5)
1.4 (1.2–1.7)
1.3 (1.0–1.7)
1.2 (1.0–1.6)
1.1 (0.9–1.2)
1.1 (0.8–1.6)
4.8 (2.6–8.2)
Note: If a twin pregnancy risk is, indeed, excessive, the relative risk (RR) of a twin pregnancy delivery has to exceed the RR
of two singleton pregnancy deliveries combined (for further details, see text). This means that only a RR R2.1 denotes
excessive twin pregnancy risk.
a
Relative risk (RR) and 95% confidence interval (CI) in comparison with singleton pregnancies.
b
Statistically significantly lower in IVF-conceived twins (P< .003).
Gleicher. Twin pregnancy after IVF. Fertil Steril 2008.
Fertility and Sterility
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assisted reproduction showed statistically significantly worse
perinatal outcomes than spontaneously conceived singletons.
In contrast, twin pregnancies after assisted reproduction
demonstrated an approximately 40% lower perinatal mortality than spontaneously conceived twins (see Table 1). Fitzsimmons et al. (27) reported similar conclusions in the late 1990s.
As most published perinatal outcome comparisons between singleton and twin pregnancies are based on spontaneous conceptions, these observations have great importance.
When applied to IVF, these data suggest that the outcome
benefits of singletons, which are worse after IVF (28), have
been greatly exaggerated and those of twins, which are better
after IVF (28), have been minimized.
The Helmerhorst et al. (28) perinatal mortality data cannot
necessarily be extrapolated to either perinatal morbidity or
maternal outcomes, but these observations nevertheless
suggest that data from spontaneous conceptions should be
statistically corrected when applied to outcome assessments
after assisted reproduction. As an intellectual exercise, Table 1
thus presents the outcome data corrected by 40%, fully recognizing that perinatal mortality data cannot necessarily
be extrapolated to other adverse outcomes in offspring and
mothers. Other outcome differences may be less divergent
than perinatal mortality, but one can equally argue that some
differences may be actually even greater. Such an argument is
best supported by the observation that singleton IVF pregnancies demonstrate actually much worse outcomes than spontaneously conceived singleton pregnancies (28).
Lower maternal and neonatal risks should not be surprising
because IVF patients usually are of higher socioeconomic
status than women who spontaneously conceive (41). Their
IVF twin pregnancies are diagnosed earlier and can be
expected to receive earlier and overall better care. Moreover,
younger women can be expected to have the larger percentage of monochorionic twins, representing a higher perinatal
risk (25, 27). That this outcome benefit is not apparent in singleton pregnancies—and, indeed, turns into a disadvantage—
is usually attributed to older age and underlying medical
conditions in IVF mothers (28), though one very recent study
suggested that outcomes of singleton IVF pregnancies also do
not have to be inferior to spontaneously conceived singletons
(42).
The most surprising finding of our literature review was,
however, that not even one study has compared pregnancy
outcomes corrected for the number of children born. Van
Wely et al. (36) are the only ones to point out that most
twin pregnancies result in the birth of two healthy children
and that this fact deserves consideration. Not surprisingly,
they conclude that twin pregnancies should not necessarily
be considered adverse outcomes of assisted reproductive
technologies.
As Table 1 demonstrates, outcome risks of twins have
uniformly been overestimated: various twin pregnancy risks,
except for minor exceptions, do not exceed relative risks of
2.0, representing the combined risk of two singleton pregnan4
Gleicher and Barad
Twin pregnancy after IVF
cies required to achieve the same outcome (two delivered
children) as one twin delivery. Assessed in such a way, risks
no longer demonstrate meaningful increases for twin pregnancies in either mothers or infants—and they often are lower
than with two singleton deliveries. If we then further consider
that IVF singleton pregnancies demonstrate higher adverse
outcomes than spontaneously conceived singletons (28), the
only remaining conclusion is that twin pregnancies (at least
after IVF) do not represent higher overall outcome risks per
newborn than singleton pregnancies.
This observation, of course, outright invalidates the principle argument in the literature of higher twinning outcome
risks after assisted reproduction and thus also contradicts
the information that is routinely provided to the public in
support of single-embryo transfer.
The Cost Argument
Another frequently heard argument in favor singleton deliveries involves the allegedly higher costs for twin outcomes
after infertility treatments (43–48). However, once again the
literature uses incorrect statistical considerations. Analogous
to the risk evaluations, cost also correctly should be calculated
in reference to outcomes; that is, cost assessments that reference pregnancy rather than the delivered child do not make
sense. They quite obviously should be calculated in reference
to the ultimate outcome benefit—the number of newborn
infants—yet not a single study has done so. This alone would
most likely eliminate the claimed cost advantages of singleton
pregnancies.
The published cost-effectiveness data suffer from an even
larger statistical error: if true costs and benefits are to be
compared between singleton and twin outcomes then both
have to be considered per lifetime. Not a single published
study has done that. Cost comparisons usually address infertility treatment costs (very short-term costs) (43, 47), perinatal
and neonatal costs (short-term costs) (43, 44, 46–48), or limited follow-up medical costs (intermediate-term costs) (45);
but they never address the long-term societal cost and benefits
such as long-term medical costs and long-term earning power.
Even in the absence of adequate studies, when the potential
long-term earning power of a (second) human being is considered after twin delivery in the presence of a very low risk of
lifelong handicaps (see Table 1), we conclude that twins offer
considerable economic benefit to society over singleton deliveries. This argument is further enhanced in developed countries that are demonstrating negative population growth and
are actively seeking ways to reverse low birth rates (48, 49).
Further Arguments in Favor of Twinning
The strongest argument in favor of twinning may be the infertile woman herself. Since the initial report on the topic in the
mid-1990s (22), it has become well recognized that a high
percentage infertility patients want twin pregnancies. Some
studies have argued that patient desires may be affected by
the degree of medical knowledge about risks associated
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with twin pregnancies, but practically all studies on the subject have had to acknowledge varying degrees of desire for
twinning in infertile patients (50–53). This is quite remarkable when we consider that the risk representations to patients
have quite obviously been misleading and have biased
patients against twin deliveries.
A desire for twins appears especially logical when associated with advanced female age and/or long-standing infertility
(22). Thus, a minority of professional opinion has recently
questioned whether twin pregnancies after IVF should be considered an adverse outcome (36, 54, 55). At the same time, the
increased psychological and economic pressures from multiple deliveries (56) and the need to reconcile a couple’s position
in regards to acceptable risk (57) have to be acknowledged.
A desire for twin delivery also appears logical when we
consider that no infertile patient can be guaranteed that that
she will conceive successfully a second time. Infertility patients are highly educated and well aware of this fact, as documented by reports that they are willing to take very specific
risks rather than face the chance of no pregnancy at all (53).
CONCLUSIONS
We have demonstrated that widely held opinions about excessive risks and costs from twin deliveries after infertility treatments are likely incorrect. In interpreting the published data,
our conclusions are logical and appear statistically correct.
Ideally, and as a more evidenced way of supporting this point,
a prospective randomized study of patients undergoing one
2-ET versus two (or more) single-embryo transfers could
be conducted to match patients for the same outcome (two
children). Such a study would be at best difficult and most
likely would be impossible to design.
How the very basic conceptual flaw we have discussed
could enter the mainstream of professional thinking deserves
some further exploration. For obstetricians, a comparison of
maternal and neonatal outcomes after singleton and twin
pregnancies does make sense; they mainly treat women after
pregnancy has already been established, and they attempt to
maximize outcomes by minimizing risks for each gestation.
The paradigm used for spontaneous conceptions is based
on post factum (after pregnancy has been established) interventions, and, in approximately 99% of cases, it is based on
singleton delivery (58). In infertile patients, circumstances
are very different.
The conceptual error seems to have arisen from the assisted reproduction profession (perinatologists and reproductive
endocrinologists alike) applying the obstetric paradigm to
a completely different patient population. In the majority
of cases, women who prospectively (and usually not
spontaneously) attempt to conceive want more than one child
and, depending on the fertility treatment, have the option
(by some called risk) of choosing different probabilities of
multiple births. This latter scenario clearly reflects different
circumstances and requires a different treatment paradigm.
Fertility and Sterility
The situation we have described offers a warning beyond
the limited confines of infertility therapy, applicable to medicine in general: treatment paradigms are population specific
and cannot be automatically transferred. How costly such an
error can be is demonstrated by this example: unwarranted
attempts to reduce twin pregnancies after IVF have been
shown to reduce overall pregnancy chances with IVF (19–21,
59). Nothing is as valuable to the infertile patient as the
opportunity to conceive (53). The widely propagated practice
of single-embryo transfer, which has been questioned in its
ability to reduce twinning risk (60), should be discouraged
unless patients have clear medical contraindications to twin
pregnancies or only desire a single child for social reasons.
Inadvertent paradigm switches occur not infrequently
in medicine. In infertility, another example has recently
attracted attention, when preimplantation genetic screening
of embryos for chromosomal abnormalities was reported to
actually decrease rather than improve pregnancy chances
with IVF (61).
Because IVF allows for relative control over twinning
chance (16), these data also suggest that the procedure
deserves further investigation as a potentially useful tool
for safe, cost-effective improvement in population growth
in countries with undesired low birth rates (49). In such
countries, governments may find that subsidizing IVF may
represent a cost-effective tool in their attempts at improving
birth rates (49).
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