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

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
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
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
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]
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.
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.
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.
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
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
Adverse outcomes with twins delivered.
Sibai et al., 2000 (31)a
MacKay et al., 2006 (26)
Maternal mortality
Fitzsimmons et al., 1998 (27)
Perinatal mortality/1000b
Helmerhorst et al., 2004 (28)a
Very 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
Placental abruption
Postpartum hemorrhage
Pinborg et al., 2004 (40)a
Birthweight <2500 gram
Birthweight <1500 gram
Gestational age 32—37 weeks
Gestational age <32 weeks
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)
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 (2.0–2.6)
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.
Relative risk (RR) and 95% confidence interval (CI) in comparison with singleton pregnancies.
Statistically significantly lower in IVF-conceived twins (P< .003).
Gleicher. Twin pregnancy after IVF. Fertil Steril 2008.
Fertility and Sterility
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
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
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
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
Vol. -, No. -, - 2008
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).
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).
1. Kogan MD, Alexander GR, Kotelchuk M, MacDorman MF, Buekens P,
Martin JA, et al. Trends in twin birth outcomes and prenatal care utilization in the United States, 1981–1997. JAMA 2000;283:335–41.
2. Fauser BCJM, Devroey P, Macklon NS. Multiple birth resulting from
ovarian stimulation for subfertility treatment. Lancet 2005;365:1807–16.
3. Jones HW Jr. Iatrogenic multiple births: a 2003 checkup. Fertil Steril
4. Jones HW Jr, Schnorr JA. Multiple pregnancies: a call for action. Fertil
Steril 2001;75:11–3.
5. Dickey RP. A year of inaction on high-order multiple pregnancies due to
ovulation induction. Fertil Steril 2003;79:14–6.
6. Seoud MA, Toner JP, Kruithoff C, Muasher SJ. Outcome of twin, triplet,
and quadruplet in vitro fertilization pregnancies: the Norfolk experience.
Fertil Steril 1992;57:825–34.
7. Conde-Agudelo A, Belizan JM, Lindmark G. Maternal morbidity and
mortality associated with multiple gestations. Obstet Gynecol 2000;95:
8. Gleicher N, Oleske DM, Tur-Kaspa I, Vidali A, Karande V. Reducing the
risk of high-order multiple pregnancy after ovarian stimulation with
gonadotropins. N Engl J Med 2000;343:2–7.
9. Dickey RP, Taylor AN, Lu PY, Sartor BM, Rye PH, Pyrzak R. Risk factors for high-order multiple pregnancy and multiple birth after controlled
ovarian hyperstimulation: results of 4,062 intrauterine insemination
cycles. Fertil Steril 2005;83:671–83.
10. Jones HW Jr. Multiple births: how are we doing? Fertil Steril 2003;79:
11. Bardis N, Maruthini D, Balen AH. Modes of conception and multiple
pregnancy: a national survey of babies born during one week in 2003
in the United Kingdom. Fertil Steril 2005;84:1727–32.
12. Schieve LA. The promise of single-embryo-transfer. N Engl J Med
13. Veleva Z, Vilska S, Hyd_en-Granskog C, Tiitinen A, Tapanainen JS,
Martikainen H. Elective single embryo transfer in women aged 36-39
years. Hum Reprod 2006;2098–102.
14. De Neubourg D, Gerris J. What about the remaining twins since single-embryo transfer? How far can (should) we go? Hum Reprod 2006;21:843–6.
15. Karlstr}
om PO, Bergh C. Reducing the number of embryos transferred in
Sweden-impact on delivery and multiple birth rates. Hum Reprod
16. American Society for Reproductive Medicine. Guidelines on number of
embryos transferred. Fertil Steril 2004;82:773–4.
17. Templeton A, Morris JK. Reducing the risk of multiple births by transfer
of two embryos after in vitro fertilization. N Engl J Med 1998;339:
18. Meldrum DR, Gardner DK. Two-embryo transfer—the future looks
bright. N Engl J Med 1998;339:624–5.
19. Pandian Z, Templeton A, Serour G, Bhattacharya S. Number of embryos
for transfer after IVF and ICSI: a Cochran review. Hum Reprod 2005;20:
20. van Montfoort APA, Fiddelers AAA, Janssen JM, Derhaag JG,
Dirksen CD, Dunselman GAJ, et al. In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly
lower pregnancy rates compared with double embryo transfer: a randomized controlled trial. Hum Reprod 2006;21:338–43.
21. Fiddeles AAA, van Montfoort APA, Dirksen CD, Dumoulin JCM,
Land JA, Dunselman AJ, et al. Single versus double embryo transfer:
cost-effectiveness analysis alongside a randomized clinical trial. Hum
Reprod 2006;21:2090–7.
22. Gleicher N, Campbell DP, Chan CL, Karande V, Rao R, Balin M, et al.
The desire for multiple births in couples with infertility problems contradicts present practice patterns. Hum Reprod 1995;10:1079–84.
23. BabyCenter Web site. Poll: How many children do you want? Accessed
March 5, 2008. Available at:
24. BabyCenter Web site. Poll: What’s the ideal family size? Accessed
March 5, 2008. Available at:
25. Rodis JF, Egan JF, Craffey A, Clarieglio L, Greenstein RM, Scorza WE.
Calculated risk of chromosomal abnormalities in twin gestations. Obstet
Gynecol 1990;76:1037–41.
26. MacKay AP, Berg CJ, King JC, Duran C, Chang J. Pregnancy-related
mortality among women with multifetal pregnancies. Obstet Gynecol
27. Fitzsimmons BP, Bebbington MW, Fluker MR. Perinatal and neonatal
outcomes in multiple gestations: assisted reproduction versus spontaneous conception. Am J Obstet Gynecol 1998;179:1162–7.
28. Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. Perinatal outcome of singletons and twins after assisted conception: a systemic review
of controlled studies. BMJ 2004;328:261.
29. Barros Delgadillo JC, Alvarado M_endez LM, Gorbea Chavez V,
Villalobos Acosta S, Sanchez Solis V, Gavi~no Gavi~no F. Perinatal results
in pregnancies obtained with embryo transfer in vitro fertilization:
a case-control study [article in Spanish]. Ginecol Obstet Mex 2006;74:
30. Manoura A, Korakakie E, Hatzidaki E, Bikouvarakis S, Papageorgiou M,
Giannakopoulou C. Perinatal outcome of twin pregnancies after in vitro
fertilization. Acta Obstet Gynecol Scand 2004;83:1079–84.
31. Sibai BM, Hauth J, Caritis S, Lindheimer MD, MacPherson C,
Klebanoff M. Hypertensive disorders in twin versus singleton gestations.
National Institute of Child Health and Human Development Network of
Maternal-Fetal Medicine Units. Am J Obstet Gynecol 2000;182:938–42.
32. Yukobowich E, Anteby EY, Cohen SM, Lavy Y, Granat M, Yagel S. Risk
of fetal loss in twin pregnancies undergoing second trimester amniocentesis. Obstet Gynecol 2001;98:231–4.
33. Millaire M, Bujold E, Morency AM, Gauthier RJ. Mid-trimester genetic
amniocentesis in twin pregnancy and the risk of fetal loss. J Obstet
Gynecol Can 2006;28:512–8.
34. Hernandez-Diaz S, Werler MM, Mitchell AA. Gestational hypertension
in pregnancy supported by infertility treatments: role of infertility, treatments and multiple gestations. Fertil Steril 2007;88:438–45.
Gleicher and Barad
Twin pregnancy after IVF
35. Ombelet W, Martens G, De Sutter P, Gerris J, Bosmans E, Russinck G, et al.
Perinatal outcome of 12 021 singleton and 3108 twin births after non-IVF
assisted reproduction: a cohort study. Hum Reprod 2006;21:1025–32.
36. van Wely M, Twisk M, Mol BW, van der Veen F. Is twin pregnancy
necessarily an adverse outcome of assisted reproductive technologies?
Hum Reprod 2006;21:2736–8.
37. ESHRE Capri Workshop Group. Multiple gestation pregnancy. The
ESHRE Capri Workshop Group. Hum Reprod 2000;15:1856–64.
38. Pinborg A, Loft A, Rasmussen S, Schmidt L, Langhoff-Roos J,
Greisen G, et al. Neonatal outcome in a Danish national cohort of
3438 IVF/ICSI and 10,362 non-IVF/ICSI twins born between 1995
and 2000. Hum Reprod 2004;19:435–41.
39. Pinborg A, Loft A, Schmidt L, Greisen G, Rasmussen A, Andersen AN.
Neurological sequelae in twins born after assisted conception: controlled
national cohort study. BMJ 2004;329:311.
40. Pinborg A, Loft A, Nyboe Andersen A. Neonatal outcome in a Danish
national cohort of 8602 children born after in vitro fertilization or intracytoplasmic sperm injection: the role of twin pregnancy. Acta Obstet
Gynecol Scand 2004;83:1071–8.
41. Gleicher N. Strategies to improve insurance coverage for infertility
services. Fertil Steril 1998;70:1006–8.
42. De Neubourg D, Gerris J, Mangelschots K, Van Royen E,
Vercruyssen M, Steylemans A, Elseviers M. The obstetrical and neonatal
outcome of babies born after single-embryo transfer in IVF/ICSI
compares favourable to spontaneously conceived babies. Hum Reprod
43. Callahan TL, Hall JE, Ettner SL, Christiansen CL, Greene MF,
Crowley WF Jr. The economic impact of multiple gestation pregnancies
and the contribution of assisted-reproduction techniques on their incidence. N Engl J Med 1994;331:244–9.
44. Kinzler WL, Ananth CV, Vintzileos AM. Medical and economic effects
of twin gestations. J Soc Gynecol Invest 2000;7:321–7.
45. Koivurova S, Hartikainen A-L, Gissler M, Hemminki E, J€arvelin M-J.
Post-neonatal hospitalization and health care costs among IVF children:
a 7-year follow-up study. Hum Reprod 2007;22:2136–41.
46. Luke B, Bigger HR, Leurgans S, Sietsema D. The cost of prematurity:
a case-control study of twins vs singletons. Am J Public Health
47. Kjellberg AT, Carlsson P, Bergh C. Randomized single versus double embryo transfer: obstetric and paediatric outcome and cost-effectiveness
analysis. Hum Reprod 2006;21:210–6.
48. Van der Gaag N, De Jong AH. Population scenarios for the European
Union: regional scenarios. Maandstat Bevolking 1997;45:17–31.
49. Hoorens S, Gallo F, Cave JAK, Grant JC. Can assisted reproductive technologies help offset population ageing? An assessment of the demographic and economic impact of ART in Denmark and UK. Hum
Reprod 2007;22:2471–5.
50. Ryan GL, Zhang SH, Fokras A, Syrop CH, Van Voorhis BJ. The desire of
infertile patients for multiple births. Fertil Steril 2004;81:500–4.
51. Newton CR, McBride J, Feyles V, Tekpetey F, Power S. Factors affecting
patients’ attitudes toward single- and multiple-embryo transfer. Fertil
Steril 2007;87:269–78.
52. Stillman RJ. A 47-year-old woman with fertility problems who desires
a multiple pregnancy. JAMA 2007;297:858–67.
53. Scotland GS, McNamee P, Peddie VL, Bhattacharya S. Safety versus
success in elective single embryo transfer: women’s preferences for
outcomes of in vitro fertilization. BJOG 2007;114:977–83.
54. Belaisch-Allart J. Is twin pregnancy necessarily an adverse outcome of
assisted reproductive technologies? Hum Reprod 2007;22:1495.
55. Gleicher N, Barad D. The relative myth of elective single embryo transfer. Hum Reprod 2006;21:1337–44.
56. Ellison MA, Hotamisligil S, Lee H, Rich-Edwards JW, Pang SC, Hall JE.
Psychological risks associated with multiple births resulting from assisted reproduction. Fertil Steril 2005;83:1422–8.
57. Karla SK, Milad MP, Klock SC, Grobman WA. Infertility patients and
their partners: Differences in the desire for twin gestation. Obstet
Gynecol 2003;102:152–5.
58. Martin JA, Park MM. Trends in twin and triplet births: 1980–97. Natl
Vital Stat Rep 1999;14(47):1–16.
Vol. -, No. -, - 2008
59. Fiddelers AA, van Montfoort AP, Dirksen CD, Domoulin JC, Land JA,
Dunselman GA, et al. Single versus double embryo transfer: cost effectiveness
analysis alongside a randomized clinical trial. Hum Reprod 2006;21:2090–7.
60. van Moontfoort APA, Fiddeleres AAA, Land JA, Dirksen CD,
Severens JL, Geraedts JPM, et al. eSET irrespective of the availability
Fertility and Sterility
of a good-quality embryo in the first cycle only is not effective in reducing overall twin pregnancy rates. Hum Reprod 2007;22:1669–74.
61. Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B,
Korevaar JC, Verhoeve HR, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med 2007;357:9–17.