RBMOnline - Vol 7. No 5. 515542 Reproductive BioMedicine Online; www.rbmonline.

com/Article/1102 on web 8 October 2003

Report of the meeting

Infertility therapy-associated multiple
pregnancies (births): an ongoing epidemic
Eli Y Adashi1, Pedro N Barri2, Richard Berkowitz3,26, Peter Braude4, Elizabeth Bryan5, Judith Carr6, Jean Cohen7,
John Collins8, Paul Devroey9, Ren Frydman10, David Gardner11, Marc Germond12, Jan Gerris13, Luca Gianaroli14,
Lars Hamberger15, Colin Howles16, Howard Jones Jr17, Bruno Lunenfeld18, Andrew Pope19, Meredith Reynolds20, Zev
Rosenwaks21, Laura A Schieve20,26, Gamal I Serour22, Franoise Shenfield23, Allan Templeton24, Andr Van
Steirteghem9, Lucinda Veeck21, Ulla-Britt Wennerholm25

1University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Salt Lake City, Utah, USA
2Service of Reproductive Medicine, Department of Obstetrics and Gynecology, Institut Universitari Dexeus,
Barcelona, Spain
3Mount Sinai School of Medicine, Department of Obstetrics and Gynecology, New York, USA
4Guys, Kings, and St Thomas School of Medicine, London, UK
5Multiple Births Foundation, Queen Charlottes and Chelsea Hospital, London, UK
6Fitchburg, Massachusetts, USA
7Hpital de Svres, Centre de Sterilit, Paris, France
8McMaster University, Department of Obstetrics and Gynecology, Hamilton, Ontario, Canada (retired)
9Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Brussels, Belgium
10Service de Gyncologie-Obstetrique et Biologie de la Reproduction, Hpital Antoine Bclre, Clamart, France
11Colorado Centre for Reproductive Medicine, Englewood, Colorado, USA
12Unit de la Mdecine de la Reproduction, Maternit du CHUV, Lausanne, Switzerland
13Centre for Reproductive Medicine, Middelheim Hospital, Antwerp, Belgium
14SISMER Reproductive Unit, Bologna, Italy
15University of Gteborg, Sahlgrenska Hospital, Department of Obstetrics and Gynecolgy, Sweden
16Serono, Geneva, Switzerland
17Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Department of Obstetrics and
Gynecology, Norfolk, Virginia, USA
18Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 52900 Israel
19Institute of Medicine, Washington DC, USA
20Division of Reproductive Health, National Centre for Chronic Disease Prevention and Health Promotion, Centres for
Disease Control and Prevention, Atlanta, Georgia, USA
21Weill Medical College of Cornell University, Centre for Reproductive Medicine and Fertility, New York, USA
22The Egyptian IVF-ET Centre, Cairo, Egypt, al. Azhar University, the Department of Obstetrics and Gynaecology;
23The University College London Medical School, Reproductive Medicine Unit, London, UK;
24University of Aberdeen, Department of Obstetrics and Gynecology, Aberdeen, UK
25Perinatal Centre, Department of Obstetrics and Gynecology, Institute for Womens and Childrens Health,
Sahlgrenska University Hospital, Gteborg, Sweden
26Absent but manuscript submitted

Introduction 2003. In keeping with the objective of improving education

Multiple gestation is now recognized as a major problem
associated with both assisted reproductive technologies (ART)
and also with ovulation induction therapies. Although some
countries are beginning to adopt measures to address this
issue, either through legislation or the development of clinical
guidelines, there is a clear need to ensure recognition and a
consistent approach to this problem worldwide. In particular,
there is a need to educate both healthcare professionals and the
lay population that multiple gestations are not a desirable
outcome for the infertile couple.
To address these issues, the Bertarelli Foundation sponsored a
meeting of international thought leaders in the field of
reproductive medicine, which was held at Weill Medical
College, Cornell University, New York, USA, on 1213 April
This report is also be published as a supplement: Reproductive BioMedicine Online 2003, Volume 7, supplement 2.
about the problems of multiple gestation and the need to
reduce its incidence, this paper provides an overview of the
presentations during the meeting and summaries of the
discussions arising from those presentations.
The incidence and health
implications of multiple gestation
Incidence of multiple gestation following
IVF, ovulation induction and ovulation
enhancement
M Reynolds and L Schieve
Multiple births have increased markedly in the USA.
Compared with 1980, the twinning rate in 2001 was 59% 515
 Infertility therapy-associated multiple births

higher, while the triplet and higher order (triplet/+) birth rate
was 401% higher (Martin et al., 2002). One trend implicated
in the rise in multiple births is infertility treatments.
This report summarizes data from the Centers for Disease
Control (CDC) registry of ART procedures performed in the
USA on the incidence of multiple gestations following ART
procedures performed in 2000 (CDC, 2002). Factors
associated with multiple gestation risk are highlighted.
Clinics in the USA that perform ART procedures are mandated
to report success rate data annually to the CDC. The Society
for Assisted Reproductive Technology (SART) annually
creates a database of ART procedures performed in USA
clinics and shares these data with CDC. A description of this
database, estimated to include approximately 95% of all
procedures performed, has been published (Schieve et al.,
1999). ART is defined as procedures involving the handling of
both eggs and sperm in the laboratory for the purpose of
establishing a pregnancy. This includes in-vitro fertilization
(IVF) (with and without intracytoplasmic sperm injection
(ICSI)), zygote intra-Fallopian transfer and gamete intra-
Fallopian transfer (GIFT). Pregnancies with >1 fetal heart
visible on ultrasound are considered multiple gestations.
Table 1 displays data on the 81,915 ART procedures
performed in 2000 that progressed to the embryo/gamete
transfer stage. Overall, 37% resulted in a pregnancy, at least
36% of which were multiple gestations (5.9% had an unknown
number of fetuses due to early pregnancy loss).
Conservatively, the proportion of pregnancies that were
triplet/+ was 7.5%, while the proportion that were twins was
28%.
For fresh, non-donor procedures, patient age was a significant
risk factor for multiple gestations (Table 1). Women <35 years
of age had a higher multiple gestation rate (40%) than older
age groups, despite the fact that older women tended to have
more embryos transferred. Procedures using donor eggs
generally resulted in a high proportion of multiple-gestation
pregnancies (43%) with little variation by patient age,
presumably due to the use of younger women as donors.
The number of embryos transferred was also a significant risk
factor for multiple gestations independent of patient age
(Table 2). For fresh, non-donor procedures performed on
women <35 years of age, both the pregnancy rate (48%) and
the singleton pregnancy rate (29%) per transfer were
maximized when two embryos were transferred. Over a third

Table 1. Embryos transferred and pregnancy rates associated with ART transfer procedures performed in the USA
in 2000, by ART type and patient age.

Maternal No. of Average. no. Pregnancy Overall Gestation type per pregnancy
age transfer of embryos rate (per multiple
(years) procedures transferred transfer)
3/+ Twin Single Unknown

All ART 81,915 3.1 37.3 35.6 7.5 28.0 58.5 5.9
procedures
Fresh, All ages 60,780 3.2 38.3 36.0 7.6 28.4 58.2 5.8
non-donor <35 28,778 2.9 44.2 40.3 8.4 31.9 55.5 4.2
3537 14,416 3.2 39.8 35.7 8.0 27.7 58.5 5.8
3840 11,301 3.5 32.4 28.2 5.9 22.2 63.5 8.3
4142 4365 3.7 22.6 17.9 2.5 15.4 69.5 12.6
>42 2190 3.6 13.1 12.9 1.4 11.5 67.3 19.9
Thawed, All ages 11,602 3.0 25.7 25.1 5.4 19.7 67.1 7.8
non-donora <35 6165 2.9 27.1 27.8 5.9 21.8 65.4 6.9
3537 2802 2.9 26.0 22.7 4.8 17.9 70.6 6.7
3840 1729 3.2 23.3 20.2 5.5 14.7 66.4 13.4
4142 567 3.3 20.8 22.9 3.4 19.5 69.5 7.6
>42 339 3.0 17.8 20.0 1.7 18.3 73.3 6.7
Fresh, All ages 6989 2.9 51.1 42.6 9.0 33.6 52.4 4.9
donorb <35 841 2.9 53.5 42.9 8.2 34.7 52.2 4.9
3537 764 2.9 50.5 46.1 9.3 36.8 50.3 3.6
3840 1293 3.0 52.6 44.9 10.2 34.8 49.5 5.6
4142 1218 2.9 50.9 41.5 8.9 32.6 54.7 3.9
>42 2873 3.0 49.9 41.0 8.7 32.4 53.5 5.5
Thawed, All ages 2544 3.0 29.9 29.2 5.5 23.6 63.6 7.3
donora, b <35 305 3.0 28.6 27.6 3.5 24.1 67.8 4.6
3537 256 2.9 29.3 25.3 4.0 21.3 66.7 8.0
3840 408 2.9 30.7 32.0 4.8 27.2 60.0 8.0
4142 398 3.0 28.9 29.6 7.8 21.7 60.9 9.6
>42 1177 3.0 30.4 29.2 5.9 23.3 64.0 6.7
aPatient age for thawed procedures refers to age at time of transfer procedure, not age at time of retrieval.
bPatient age for donor procedures refers to the patient receiving the embryos, not the donors age.
516 ART = assisted reproductive technologies.
 Infertility therapy-associated multiple births

Table 2. Overall pregnancy and multiple gestation rates by number of embryos transferred, fresh non-donor ART transfer
procedures performed on patients <35 years of age in the USA, 2000.

No. of Fresh non-donor transfer procedure Fresh donor transfer procedures

embryos (maternal age <35 years) (all ages)
transferred
n Pregnancy Singleton Gestation n Pregnancy Singleton Gestation
ratea rateb typec(%) ratea rateb typec(%)
Twin Triplet/+ Twin Triplet/+

All transfer procedures

1 1157 18.0 15.7 2.9 0.0 148 22.3 19.6 3.0 0.0
2 9573 48.0 28.8 35.0 1.0 2516 54.9 30.3 37.9 1.2
3 11,653 45.6 24.2 31.2 11.6 2759 52.4 26.6 32.3 11.9
4 4506 41.0 20.7 30.6 14.6 1031 45.4 22.3 29.7 17.7
5 1860 39.4 18.2 29.8 18.6 528 45.3 21.6 28.5 20.5

1 extra embryo(s) cryopreserved

1 91 36.3 30.8 6.1 0.0 22 40.0
2 4907 55.9 31.7 39.1 1.1 1659 59.4 31.3 40.2 1.1
3 4431 51.8 25.4 33.4 13.3 1467 55.3 26.2 33.5 14.6
4 1220 44.6 19.2 35.3 19.1 414 50.7 22.5 31.9 21.4
5 386 48.7 21.8 29.8 19.7 166 47.0 23.5 26.9 18.0

No. of embryos cryopreserved

1 1066 16.4 14.5 2.3 0.0 126 19.1 16.7 0.0 0.0
2 4666 39.8 25.9 29.0 1.0 857 46.2 28.5 32.3 1.5
3 7322 42.0 23.5 29.6 10.4 1292 49.1 27.0 30.8 8.5
4 3286 39.6 21.3 28.7 12.8 617 41.8 22.2 27.9 14.7
5 1474 36.9 17.2 29.8 18.2 362 44.5 20.7 29.2 21.7

aPregnancy rate calculated as number of pregnancies per ART transfer procedure performed.
bSingleton rate calculated as number of singleton gestations per ART transfer procedure performed.
cTwin (%) and triplet/+ (%) gestation type refers to the percentage of pregnancies that were twin and triplet/+, respectively.
ART = assisted reproductive technologies.

of the pregnancies resulting from the transfer of two embryos
were twin gestations (35%), while 1% were triplet/+ due to
monozygotic twinning. Transferring a third embryo increased
the proportion of triplet/+ gestations to 12%, while conferring
no benefit to pregnancy success rates.
Limiting analyses to procedures in which patients elected to
transfer fewer embryos than were available and had their non-
transferred embryos cryopreserved, a presumably better
prognosis group, revealed an identical pattern with respect to
the overall pregnancy rate being maximized at two embryos
transferred (56%). However, the singleton pregnancy rate for
two embryos (32%) was not an improvement over the rate for
single-embryo transfers (SET, 31%). Transferring a third
embryo increased the proportion of triplet/+ gestations to 13%
from 1%, without improving the pregnancy rate (52%). For
procedures in which no extra embryos were cryopreserved,
transferring a third embryo increased the overall pregnancy
rates two percentage points at the cost of a nine percentage
point increase in the proportion of triplet/+ gestations. The
pattern of results for donor transfer procedures was similar:
transferring a third embryo increased the risk for triplet/+
gestations while conferring no benefit for success rates for
procedures with extra embryos cryopreserved and a minimal
increase in success rates for procedures with no cryopreserved
embryos.
Translating multiple-gestation rates into numbers of live-born
infants allows for a more direct assessment of the impact ART
has on maternal and infant health outcomes. In 2000, ART
accounted for nearly 1% of all USA births (CDC, 2002).
However, these infants represented an estimated 13.6% of
multiple births that year, 11.8% of twins and 42.5% of triplet/+
infants (Reynolds et al., 2003a).
Some have suggested that universal ART insurance coverage
will help address the multiple gestation problem by reducing
the pressure couples experience to achieve pregnancy within a
single procedure leading to the transfer of more embryos
(Jones, 2003). However, analysis of the three states with ART
insurance mandates that provide the most comprehensive
coverage revealed that coverage is not necessarily associated
with a reduction in either embryos transferred or multiple
gestations (Reynolds et al., 2003b). Thus, insurance mandates
may not be sufficient to reduce multiple gestation rates in the
absence of an attitude shift among patients and providers to
view treatment success in terms of singleton pregnancies.
Finally, it should be noted that no population data are available
regarding the incidence of multiple gestations among women
undergoing non-ART infertility treatments, including
intrauterine insemination (IUI) and ovulation-enhancing
drugs, in the USA. 517
 Infertility therapy-associated multiple births

Chairmans post-meeting insertion
At the request of the chairman, European data on the incidence
of multiple gestations are included in this report for
comparison with those generated by the CDC registry. Data
from 1999 were collected from national registries and were
collated in a European Society of Human Reproduction and
Embryology (ESHRE) report (The European IVF-monitoring
programme for ESHRE, 2002) (Table 3). A total of 538 clinics
from 22 countries reported 258,460 cycles; eight countries
with complete registration contributed data on 99,629 cycles
covering a population of 106 million and representing 943
cycles/million inhabitants. After IVF and ICSI, the distribution
of transfer of one, two, three or more than three embryos was
11.9, 39.2, 39.6 and 9.3%, respectively, although it was noted
that huge differences between countries were seen. For IVF,
the clinical pregnancy rate/transfer was 27.7%. For ICSI, the
corresponding rate was 27.9%. Delivery rates for singleton,
twins, triplets and quadruplets after IVF and ICSI combined
were 73.7, 24.0, 2.2 and 0.1%, respectively; the total multiple
delivery rate was 26.3%.
Health and development of twins, triplets
and higher-order multiple births
U-B Wennerholm
It has been recognized for many years that multiple gestations
are associated with increased risks to the health of both mother
and babies when compared with singleton pregnancies.
Although twins are often regarded as an acceptable, or even
desirable, outcome after infertility treatment, such pregnancies
actually carry an increased risk of infant mortality and
morbidity compared with a singleton pregnancy.
Maternal morbidity and mortality
Multiple pregnancies are associated with a range of well-
documented risks to the health of the mother. These include
hypertensive disorders, thrombo-embolism, urinary tract
infection, anaemia and vaginal-uterine haemorrhage (placental
abruption, placenta previa), and fluid overload in association
with parental tocolysis (Senat et al., 1998; Sebire et al., 2001).
Women carrying multiple pregnancies are also more likely to
require long periods of bed rest, hospitalization, administration
of medication to prevent pre-term labour, surgical procedures,
such as emergency Caesarean section and cerclage, and to
undergo premature labour and delivery. The magnitude of all
these risks increases in line with the number of fetuses.
Multiple pregnancies also carry an increased risk of maternal
mortality when compared with singleton pregnancies,
especially in developing countries. Mortality rates of 14.9 and
10.2 per 100,000 pregnancies have been reported for multiple
pregnancies in Europe in 1994 and in France, respectively,
compared with rates of 5.2 and 4.4 for singleton pregnancies in
the same periods (Senat et al., 1998). In contrast, maternal
mortality rates of 77 per 100,000 pregnancies were associated
with multiple pregnancies in Latin America between 1985 and
1997 compared with a rate of 43 for singleton pregnancies
(Conde-Agudelo et al., 2000).

Table 3. The European IVF-monitoring programme (EIM), for the European Society of Human
Reproduction and Embryology (ESHRE), 2002.

Embryos transferred after Infants born as singletons, twins, triplets and

IVF and ICSI (%) quadruplets after IVF and ICSI (%)
1E 2E 3E 4E Singletons Twins Triplets Quadruplets

Belgium 10.6 46.7 34.0 25.4

Czech Republic 10.2 18.9 52.9 18.0 62.0 41.3 14.6 1.9
Denmark 60.8 38.6 0.6 0.0
Finland 21.1 74.9 5.4 0.0 60.1 37.9 1.9 0.0
France 13.8 42.3 37.2 6.7 59.3 37.7 3.1 0.0
Germany 11.1 37.3 51.6 0.0 58.4 35.2 6.3 0.0
Greece 10.0 20.0 32.2 37.8 58.6 39.8 1.6 0.0
Hungary 7.8 16.9 47.6 27.7 41.6 44.4 13.1 0.9
Iceland 11.1 67.7 21.2 0.0 67.2 28.4 4.5 0.0
Ireland 8.2 22.0 67.3 2.5 55.6 36.3 8.1 0.0
Italy 11.3 31.1 40.9 16.9 57.7 33.6 8.1 0.6
The Netherlandsa
Norway 59.0 39.5 1.4 0.0
Poland 16.3 64.0 14.8 4.8 62.0 33.2 4.9 0.0
Portugal 12.8 30.1 45.7 11.0 51.9 42.0 5.0 1.1
Russia 12.0 20.0 22.5 45.5 55.9 33.8 9.8 0.5
Slovenia 22.5 62.4 15.1 0.0 79.0 19.0 1.7 0.0
Spain 8.6 16.3 45.6 29.4 48.5 40.3 10.7 0.5
Sweden 11.2 84.3 4.5 0.0 60.3 38.8 0.9 0.0
Switzerland 12.9 57.1 28.1 1.9 42.5 42.5 3.1 0.0
UKa
Ukraine 6.6 15.4 15.4 59.5
All 11.9 39.2 39.6 9.3 79.0 44.4 14.6 1.9

518 ICSI = intracytoplasmic sperm injection; IVF = in-vitro fertilization.

aNo data available.

Neonatal morbidity and mortality
Recent research has shown that chorionicity rather than
zygosity determines the outcome of twin pregnancies, with
monochorionic twins being at higher risk of a poor outcome
than dichorionic twins (Sebire et al., 1997). Fetal loss before
24 weeks gestation, perinatal mortality, pre-term birth (<32
weeks) and birth weight below the fifth percentile are all more
common in monochorionic twins. Chorionicity can be
accurately determined antenatally by ultrasonic examination
of the junction of placenta and the inter-twin membrane at
1114 weeks of gestation. Approximately 20% of all twins are
monochorionic, with the proportion being higher in
spontaneous twins (30%) compared with those resulting from
ART (3.7%) (Derom et al., 2001).
Many of the perinatal complications that are seen in infants
from multiple pregnancies are attributable to the fact that they
are more likely to be born prematurely and with a low birth
weight than babies from singleton pregnancies. Data from the
National Vital Statistics Report for the USA in 2001 show that,
in general, the gestational age at birth was reduced by 3 weeks
for every additional fetus, while the birth weight of the average
triplet was approximately half of that for the average singleton
(Table 4) (Martin et al., 2002).
All mortality rates, including stillbirths, early neonatal deaths,
late neonatal deaths and infant mortality, are higher in multiple
pregnancies, and the rates increase with the number of fetuses.
For example, data from a study performed in England and
Wales showed that, despite being relatively rare, multiple
births make a large contribution to such rates. Although
multiple births represented only 2.5% of all births, they
accounted for 8% of all stillbirths, 19% of all neonatal deaths
and 7% of all post-neonatal deaths in 1991 (Doyle, 1996). The
effect of multiple gestations was most marked for neonatal
deaths, with the rate for twins being seven times higher, and
that for triplet/+ gestations being more than 20 times higher
than the rate for singleton pregnancies. More recent data from
the USA show that the infant mortality rate in 2000 was 6.1 per
1000 live births for singleton pregnancies and 31.1 for
multiple pregnancies (Russel et al., 2003). As in the UK, this
rate increased with the number of fetuses, from 28.9 per 1000
live births for twins, to 63.2 for triplets and 95.5 for
quadruplets. Both this study and one performed in Sweden
Table 4. Gestational age and birth weight characteristics by plurality. Data from the National Vital Statistics
Reports for the USA for 2001 (Martin et al., 2002).
Singletons Twins
Number 3,897,216 121,246
Gestational age (weeks)
<32 (%) 1.6 11.8
<37 (%) 10.4 57.4
Mean (SD) 38.8 (2.5) 32.0 (4.0)
Birth weight (g)
<1500 (%) 1.1 10.2
<2500 (%) 6.0 54.9
Mean (SD) 3339 (573) 2353 (647)
SD = standard deviation.
Infertility therapy-associated multiple births
(Rydhstrem and Heraib, 2001) found that the risk of mortality
is greater for same-sex twins than for different-sex pairs.
Finally, a large population-based cohort of over 1,000,000
births in Australia and the USA, of which more than 20,000
were twins, found that twins had an approximately fivefold
increase in the risk of fetal death and a sevenfold increase in
the risk of neonatal death when compared with singletons.
However, the risk varied between twin pregnancies, with
second-born twins, twins from same-sex or growth-discordant
pairs, and twins whose co-twin died in utero having an
increased risk of death (Scher et al., 2002).
Low birth weight and pre-term delivery are the major factors
accounting for the excess in neonatal morbidity that is seen in
the infants from multiple births. Thus, in one study, although
twins constituted only 2.4% of all neonates, they accounted for
7.9% of those with a low Apgar score at 5 min, 11.4% of those
with grade 34 intraventricular haemorrhage (IVH), 7.6% of
those with sepsis, 9.9% of those with necrotizing enterocolitis
and 13.8% of cases of respiratory distress syndrome (RDS)
(Gardner et al., 1995). Pre-term twins had a higher incidence
of RDS than pre-term singletons, but this difference
disappeared after stratification for gestational age. There are
few data relating to neonatal morbidity in triplet/+ births.
Rates of RDS ranging from 8.9 to 43.4% have been reported
for triplets, and from 34.8 to 75% for quadruplets, while IVH
grade 34 has been diagnosed in up to 7.7% of triplets and
8.7% of quadruplets. A study that compared neonatal
morbidity in triplets with that in singletons and twins, using
logistic regression analysis and correcting for gestational age,
showed that incidences of retinopathy of prematurity, patent
ductus arteriosus and mild IVH (grade 12) were significantly
higher in triplets than in singletons (Kaufman et al., 1998). As
a result of these problems, many infants from multiple
pregnancies require treatment and extended care in neonatal
intensive care units (NICU). In one study, 15% of singletons,
48% of twins and 78% of triplets/+ required treatment in a
NICU (Callahan et al., 1994).
Paediatric morbidity
Even if infants from multiple pregnancies are delivered alive
and survive the early post-natal period, they have an increased
risk of long-term medical and developmental problems. In
particular there is a risk of neurological impairment, which
Triplets Quadruplets Quintuplets
6885 501 85
36.7 64.5 78.6
92.4 97.8 91.7
35.4 (3.7) 29.6 (4.1) 29.1 (3.9)
34.8 68.4 77.4
94.0 98.4 91.7
1678 (574) 1290 (549) 1269 (676)
519
 Infertility therapy-associated multiple births
ranges from gross clinical impairment to minor and probably
subclinical abnormalities. As for the other risks associated
with multiple pregnancies, the risk of handicap increases with
the number of fetuses. Twins have been shown to have a 1.4-
fold increase in risk for all handicap compared with singletons,
with risks 1.7 and 1.3 times greater for severe and moderate
handicap, respectively; while the risks for triplets are 2.0-fold
higher for all handicap, and 2.9 and 1.7 times greater for severe
and moderate handicap when compared with singletons (Luke
and Keith, 1992). In a study of infants from multiple
pregnancies born in Japan after 1977, Yokoyama et al. (1995)
found that the incidence of handicap increased from 3.7% in
twins to 8.7% in triplets, 11.1% in quadruplets and 10.0% in
quintuplets. At least one child was handicapped in 7.4% of
twin pregnancies, 21.6% of triplet pregnancies, and 50% of
quadruplet and quintuplet pregnancies.
Cerebral palsy is one of the most significant neurological
impairments associated with multiple births, and a consistent
finding in the literature is that its incidence increases in line
with the number of fetuses. The risk of cerebral palsy in twins
is approximately five times that in singletons, and in triplets it
is between 17-fold and 20-fold greater than in singletons. A
study performed in Western Australia has proved particularly
informative with respect to the incidence and risks of cerebral
palsy in infants resulting from multiple pregnancies, by
presenting the data according to rate per 1000 live births, per
1000 first-year survivors and per 1000 pregnancies (Figure 1)
(Petterson et al., 1993). When the rate of cerebral palsy for
singletons was standardized to 1, it was shown that twins were
4.6 times more likely to have cerebral palsy, compared with
singletons, on the basis of 1000 live births or 1000 first-year
survivors, but this risk increased to 8.3 times when calculated
per 1000 pregnancies. The increased risks over singletons are
even more pronounced in triplets.
In the UK, Pharoah and Cooke (1996) found in a population-
based study that the prevalence of cerebral palsy per 1000
first-year survivors in singletons was 2.3 [95% confidence
interval (CI), 2.12.5], in twins 12.6 (9.716.1) and triplets
44.8 (16.695).
Mental and language development may also be impaired in
infants from multiple pregnancies. In the La Trobe twin study,
performed in Australia, male twins were especially delayed in
Figure 1. The incidence of cerebral palsy in singletons, twins
and triplets born in Western Australia between 1980 and 1989
520 (Petterson et al., 1993).
their language development. Among male twins aged 30
months, language development was delayed by 8 months in
comparison with matched singletons (Hay et al., 1987a).
Similarly, a study of triplets performed in Sweden at 46 years
of age and again at 9 years of age found that they displayed
motor and coordination difficulties compared with singletons
of the same age, despite careful selection criteria to ensure that
only uncomplicated triplets were included in the study (Alin
kerman et al., 1995).
The psychological impact of multiple
gestation on the host family
E Bryan
Many parents undergoing treatment for infertility may have
unrealistic expectations of pregnancy and parenthood. For
them, the prospect of twins or triplets may seem like the
realization of a long-held dream. However, the practical,
financial and emotional difficulties of caring for two or more
babies at the same time may be particularly difficult for them
to imagine.
The parents
Many parents are unprepared for the impact that the birth of
twins can have on the relationship with their partner. In
particular, the father may be surprised by the amount of help
he has to provide with baby care, and he may find it difficult
to accept how much of the mothers attention and emotions are
focused on the babies. A preliminary study of couples that had
twins following IVF indicated that they found parenting
considerably less rewarding than they had expected (Cook et
al., 1998). Furthermore, parenting stress was found to be
greater for families with twins following IVF compared with
those with spontaneously conceived twins. This difference
may have been due to a sense of failure to reach the high
standards of parenting they had dreamt of for so long.
Different strains are placed on the parents in the immediate
post-natal period and through later childhood. Often, sick pre-
term infants require treatment in the NICU, and this may
require transfer to separate units, as sufficient intensive care
cots may not be available in a single unit. This places great
strain on both parents in terms of logistics, and emotional
stress on the mother who is unable to keep all her babies
together; mothers are known to find it more difficult to relate
to babies from whom they have been separated during their
first days.
Mothers of twins are more likely to be attracted to the healthier
infant (Goldberg et al., 1986), and this may create a further
emotional strain if one of the babies is clearly sicker than the
other. This in turn may provoke feelings of guilt in the mother.
Although the long-term effects of early mothertwin
relationships on subsequent development have yet to be
established, a recent study of pre-term singletons and twins
found that mothers of twins showed fewer initiatives and
responses to their babies, and they were less responsive to both
positive signals and to crying. Follow up when the children
were 18 months of age revealed that the cognitive
development of the twins was less advanced than that of the
singleton controls, and that maternal behaviour in the newborn

period was predictive of the level of development of the
children (Ostfeld et al., 2000). Other negative influences on
development include the increased fatigue suffered by mothers
of twins and also depression well beyond the infancy period
(Thorpe et al., 1991).
An additional potential source of stress in the perinatal period
is the death of one or more babies. Parents who lose one or
more babies from a multiple birth, but still have a surviving
infant, have special problems as they are left with a constant
reminder of the dead child, especially if it is a monozygotic
twin (Bryan, 1999a). The loss of babies from a higher multiple
set can be particularly difficult. After many years of infertility,
the mother may have three, four or more live babies but then
has to watch as one or more of them die soon after birth, or
more slowly over the following weeks or months. Despite these
deaths, a couple left with one or two babies often receives
remarkably little sympathy about the death of the others.
Outside the immediate post-natal period, the practical
problems of caring for two or more babies continue, even
when all are healthy. No mother can carry three babies at once,
and many mothers cannot take their babies out of the home and
so become housebound and isolated as a result. A study of
families with triplets in the UK repeatedly found that help for
families, both statutory and private, had been inadequate in
amount and slow to arrive. Parents often became ill and
exhausted before help was provided (Botting et al., 1990).
There are also insufficient hours available for a mother to
provide the care required by triplets. Thus, a study by the
Australian Multiple Births Association showed that 197.5 h (of
the 168 available) per week were required to care for 6-month-
old triplets and to carry out the necessary household tasks
(AMBA, 1984). Many parents become frustrated by their
inability to give each child the individual attention that he or
she deserves. Even in those families with material resources
and plenty of help, emotional stress, sometimes requiring
psychiatric treatment, is not uncommon (Garel et al., 1997a).
The children
The children resulting from a multiple gestation suffer from
having to share their mother with their co-twin, or triplets.
Even if all the children are healthy, their parents are unable to
provide them with the same level of attention that is given to
infants from singleton births. However, the problems are
exacerbated if one child is handicapped in some way. The child
with the disability finds it difficult to understand why he and
not his twin is affected. Feelings of jealousy and anger are not
uncommon, and depression may also develop (Bryan, 1999b).
Conversely, the unaffected twin will be jealous of the extra
care and attention that are given to his co-twin during the early
years, although this is often followed by guilt and an excessive
burden of responsibility in later life.
The child whose twin died in the perinatal period also has
difficulties to overcome. He may suffer not only from the loss
of his companion but also the grief of his parents. He may feel
angry with the twin for deserting him and/or with his parents
for allowing the death to happen. However, others may feel
guilty that they have survived while their co-twin died
(Woodward, 1998; Bryan, 1999a).
Infertility therapy-associated multiple births
The siblings
Although it has received less attention than the impact of
multiple births on the parents, the effect on other children in
the family also needs to be considered. In particular, a single
toddler who has been the centre of the family will find it
difficult to adapt to the arrival of attention-attracting twins or
triplets. It has been shown that a sibling is likely to be more
disturbed by the arrival of twins than of a single sibling, and
that behaviour problems in the older child are more common
following a multiple birth (Hay et al., 1987b).
Multifetal pregnancy reduction:
indications and complications
R Berkowitz (Dr Berkowitzs paper was discussed in
his absence)
Multifetal pregnancy reduction (MPR) is a procedure
developed in the 1980s to improve pregnancy outcome in
women with high-order multiple pregnancies, by physically
reducing the number of fetuses in the uterus. Although it
employs a similar technique, MPR differs from selective
termination of one or more fetuses that are known to be
abnormal in a multiple pregnancy. MPR assumes that all the
fetuses are normal, and the intent of the procedure is to
produce the outcome that would have been achieved if fewer
fetuses had originally been conceived.
There is a substantial body of evidence to show that MPR can
prolong gestation of the remaining fetuses and so reduce the
risks associated with early pre-term delivery. Reduction of
triplet pregnancies to twins typically increases gestation by 2
3 weeks, and reduction to twins or a singleton from higher-
order pregnancies prolongs the pregnancy even more (Stone et
al., 2002; Rochon and Stone, 2003). However, MPR, like any
invasive procedure, can lead to unintended loss of the entire
pregnancy. In one series of 1000 consecutive cases performed
transabdominally, the pregnancy loss rate before 24 weeks was
5.4% (Stone et al., 2002). Of these, 15% occurred within 4
weeks of the procedure, but more than half occurred after 8 or
more weeks following the MPR. The loss rate was lowest in
patients starting with twins and highest for those starting with
six or more fetuses. Evidence strongly suggests that the loss
rates following MPR improve with increasing operator
experience. In expert hands, the risk of losing the pregnancy
within 1 month of the procedure is probably less than 1%, and
the overall risk of pregnancy loss seems to be comparable to
that of the spontaneous loss rate in women who initially
conceive twins. Furthermore, in experienced hands the loss
rates are not increased if chorionic villous sampling (CVS) is
performed prior to an MPR (Eddleman et al., 2000).
Therefore, in view of the advantages of knowing whether any
fetuses are karyotypically abnormal before doing a reduction,
women at increased risk for having a fetus with an aneuploidy
may be offered CVS before having an MPR.
Despite the possible benefits in terms of prolonging gestation,
the decision to proceed with MPR is never easy. As it is a form
of elective abortion, the procedure is absolutely unacceptable
to people who cannot condone termination of a fetus under any
circumstances. Even those who do not have strong ethical
objections to the procedure will be faced with emotional 521
 Infertility therapy-associated multiple births
difficulties. The overwhelming majority of patients who are
candidates for MPR have conceived following infertility
therapy and are delighted to have achieved their goal of
becoming pregnant. The prospect of electively terminating one
or more of the fetuses at a time when everything is progressing
satisfactorily, in order to reduce the chances of a possible
adverse outcome (which might not occur), is extremely
difficult for them. Psychological evaluations of women who
have undergone MPR have found that most patients
experience feelings of sadness and guilt following the
procedure, although these do not normally persist beyond 2
years (Schreiner-Engel et al., 1995; Garel et al., 1997b; Bergh
et al., 1999a). However, all of the couples involved in these
studies emphasized their strong belief that high-order
pregnancies should be avoided.
Although there are no data relating to the total numbers of
women who undergo MPR each year, it is probable that
significant numbers of couples and their physicians are relying
on this procedure as a solution to the problem of high-order
multiple pregnancies following ART. However, in view of the
ethical and emotional problems raised by MPR, it is clear that
this procedure should not be viewed as the optimal solution to
the problem of conceiving three or more fetuses. The objective
of the reproductive endocrine community must therefore be to
identify and apply mechanisms to minimize the numbers of
iatrogenic triplets and completely eliminate higher-order
pregnancies in couples undergoing ART, rather than relying on
MPR as a safety net when those conceptions occur.
Discussion
It was agreed that to adequately address the problem of
infertility therapy-associated multiple gestations, it is essential
to obtain reliable information about the contribution of
ovulation induction (OI)/ovulation enhancement (OE), as well
as IVF and related procedures. At present, however, most
countries, including the USA via the CDC, only collect data
relating to births resulting from IVF and related procedures. To
provide an estimate of the proportion of multiple pregnancies
resulting from OI/OE and from IVF and related procedures,
the CDC uses data on the incidence of multiple gestations
associated with natural conception adjusted for maternal age
from the period before infertility treatment became
widespread, and compares that with the current incidence of
multiple gestations. Once the known incidence of multiple
pregnancies attributable to IVF and related procedures is
subtracted from this figure, it is assumed that any remaining
excess in the modern data is due to OI/OE procedures.
One way in which it might be possible to obtain a better
estimate of multiple births resulting from OI/OE would be to
perform a retrospective analysis of multiple-birth parents
within a specific region or state and find out how many had
received OI/OE. Although there are concerns about potential
infringement of patient confidentiality with this approach, it
has been agreed by the authorities in Virginia that it would be
permissible to get anonymous data from the doctor who signed
the birth certificate. Indeed, it is important to know which
doctors are treating these patients (e.g. infertility specialists or
general gynaecologists), in order to ensure that education
programmes relating to the need to reduce the risk of multiple
522
gestations with OI/OE are directed towards the correct
audience(s). It must be recognized, however, that the above
course of action may not be applicable elsewhere and that
alternative means of securing reliable data may be necessary.
An alternative approach to establishing the incidence of
multiple gestations attributable to OI/OE is currently being
pursued in Israel, using the countrys existing register of low-
birth-weight births and seeking to identify how many were
spontaneous and how many resulted from IVF, OI or OE.
However, the use of birth registers does not provide the
complete answer, as a large number of fetuses are lost very
early in gestation, either through spontaneous miscarriage or
embryo reduction. As with the proportion of multiple
gestations attributable to OI/OE, the scope of this problem is
difficult to estimate. The CDC records the number of fetal
hearts present at 12 weeks and the number of babies delivered,
but it has no data relating to the source(s) of fetal loss.
It has been suggested that insurance coverage for IVF would
reduce the number of multiple gestations as compared with
privately funded treatment, because there would be less
pressure on couples to maximize the chance of pregnancy
through transfer of several embryos in each cycle. A study by
Jain et al. (2002) found that for those states in the USA in
which insurance coverage of IVF is mandated (Illinois,
Massachusetts and Rhode Island), there was increased use of
these services compared with all states in which there is no
insurance coverage, but that the number of embryos
transferred per cycle, the number of cycles resulting in
pregnancy and the percentage of pregnancies with 3 fetuses
were all lower. However, a subsequent study, which compared
the same three states with three matched non-insurance states,
found that only two of the states with insurance coverage had
a lower proportion of higher-order (3) embryo transfers, and
only one had a significantly lower rate of multiple births
(Reynolds et al., 2003b). Further analysis suggested that the
lower incidence of multiple births in this state was not due to
a reduction in the number of embryos transferred, but rather
was attributable to a higher rate of partial or complete
pregnancy loss compared with the non-insurance states.
Consequently, the latter study concluded that insurance
coverage would not reduce the number of multiple births.
In contrast to the situation within the USA, experience from
Europe suggests that in those countries where IVF is fully
supported within the healthcare system, there is a reduction in
the number of embryos transferred per cycle and that this
translates into lower multiple-birth rates. It was agreed that it
is difficult to make any generalization about the possible
impact of insurance coverage on multiple gestations, as the
details of coverage vary between states (e.g. limit on the
number of cycles covered or overall value of cover), which
will inevitably influence the overall outcome of IVF treatment.
It was agreed that there is still much to be learned about the
impact of all interventions associated with infertility treatment
upon the risks of multiple gestations and births. Thus, reliable
data are required to facilitate determination of the incidence of
multiple gestations following OI and OE as well as IVF
procedures, and also for the numbers of elective MPR
procedures and spontaneous pregnancy losses (partial and
 Infertility therapy-associated multiple births

total). Consistent data are required, possibly via registries,
from a number of different countries in order to fully
appreciate the magnitude of the problem.
Legal, ethical and economic
implications of multiple gestation
attributable to infertility therapy
Multiple gestation is an undesirable effect of infertility
treatment, and the associated medical complications such as
pregnancy loss, premature delivery, perinatal mortality and
childhood health problems can lead to psychological and
social concerns. Ultimately, the complications of multiple
gestations can have significant economic implications both for
the family involved and for the healthcare system. Therefore,
minimizing the incidence of multiple gestation would reduce
both medical complications and the psychological effects on
the family, leading to decreased costs. The infertility physician
plays an important role in ensuring that the risk of multiple
pregnancies is minimized, through education of patients, the
healthcare profession, the media, and those responsible for
producing national policies or guidelines. However, decisions
about how and whether to minimize multiple gestations are
often based on clinical data. Careful consideration should be
given to the nature and robustness of these data and, therefore,
how meaningful they are in the real world.
Table 5. Risk of multiple births according to
infertility treatment.
Infertility treatment Multiple of population frequency
Twins Triplets
Clomiphene citrate 12 200
Gonadotrophins 20 500
IVF/ICSI cycles 30 500
ICSI = intracytoplasmic sperm injection; IVF = in-vitro fertilization.
The economic consequences of multiple
gestation attributable to infertility therapy
J Collins
Multiple gestations result in higher perinatal healthcare costs
than singleton births, initially as a consequence of premature
delivery and the associated requirement for neonatal intensive
care, drug therapies and diagnostic procedures. After
discharge, further costs are incurred through treatment of
chronic health problems, including visual and developmental
disabilities. Thus, studying the hospital costs associated with
multiple births provides an indication of the resulting infancy
and childhood burden of illness (Papiernik, 1991; CDC, 2000).
The various treatments for infertility, such as clomiphene
citrate (CC) or gonadotrophins for OI/OE and ART
procedures, all carry substantial but different risks for multiple
gestations compared with the general population (Callahan et
al., 1994; CDC, 2000; Tough et al., 2000; Lynch et al., 2001).
Thus, whereas CC is the most frequently used treatment, it is
less likely to be associated with triplets than gonadotrophin
therapy or ART, both of which have a risk that is 500 times
greater than that of the general population (Table 5) (Guzick et
al., 1999; CDC, 2000; Gleicher et al., 2000; Dickey et al.,
2001; Lynch et al., 2001; Tur et al., 2001). Health, education
and social costs during infancy and childhood are higher for
the offspring of multiple pregnancies than for those of
singleton pregnancies. However, as these costs are difficult to
estimate (Papiernik, 1983, 1991), our knowledge is limited to
a few early reports, mainly from the USA, on the hospital costs
for newborns from multiple births (Table 6) (Callahan et al.,
1994; Chelmow et al., 1995; Luke et al., 1996; Ruiz et al.,
2001). In an attempt to provide a more up-to-date and realistic
estimate of the excess cost of multiple over singleton births,
the weighted average cost was calculated by projecting the
results from each study to 1999 prices, assuming an annual
inflation rate in healthcare costs within the USA of 3.5%. In
the absence of any data from any of the studies, the costs for
quadruplets were extrapolated from the singleton, twin and
triplet data. The substantial projected excess costs per family
ranged from US$43,300 for twins up to US$174,000 for
quadruplets (Table 7) (American Society of Reproductive
Medicine (ASRM)/SART, 2002).

Table 6. Newborn and maternal hospital costs per family. Although OI accounts for approximately 40% of all births
following infertility treatment (Division of Reproductive
Study year Hospital cost per family (US$) Health, National Centre for Chronic Disease Prevention and
Singleton Twins Triplets Health Promotion, 2000), published estimates of the number of
births attributable to OI vary (Callahan et al., 1994; Tough et
1991 9845 37,974 109,765 al., 2000; Lynch et al., 2001). To address such differences, a
(Callahan et al., 1994)
Table 7. Excess hospital costs per family of multiple births
1991 9326 88,891 (ASRM/SART, 2002).
(Chelmow et al., 1995)
Single Twin Triplet Quadruplet
1993 64,837
(Luke et al., 1996) Deliveries (n) 10,967 5208 760 32
Excess/delivery
1995 46,796 (US$) 43,300 120,000 174,000
(Ruiz et al., 2001) Total excess
(US$m) 225.5 91.2 5.6 523
 Infertility therapy-associated multiple births
model was devised in an attempt to estimate more accurately
the proportion of births resulting from the different OI
therapies. The model assumed that for 10,000 births following
OI, 6000 occurred after CC, and 2000 each occurred after
gonadotrophin therapy and ART procedures. The risks of
multiple births per treatment used in the model were those
presented in Table 5. Using these data, the excess cost
associated with multiple births per 10,000 births following OI
was estimated to be US$105.6 million (Table 8). In addition,
CC and ART procedures were shown to account for similar
proportions of the overall cost of multiple births after
infertility treatment.
National policies towards the prevention
of multiple gestation: a comparison of
European and US perspectives
J Cohen and H Jones Jr
Although multiple gestations may be considered a public
health issue, arguments for and against legislation or
guidelines vary considerably. For example, legislation is
helpful to ensure that the need to prevent multiple pregnancies
is made clear and transparent within individual clinics.
However, such measures may limit both the physicians
clinical autonomy and the patients rights to receive the most
appropriate treatment individualized to their particular
circumstances. Although an international consensus would be
helpful in providing a coherent message on this issue,
differences between countries in their attitudes towards the
need for measures to minimize multiple gestations are often
based upon national concerns and cultures.
The European perspective
Within Europe, there is little consensus between countries on
the prevention of multiple pregnancies. Some European
countries have passed laws aimed at reducing the number of
multiple pregnancies, for example by restricting the number of
embryos transferred, whilst others have official regulations set
by national scientific societies. Nevertheless, a number of
countries have no national restrictions, although individual
clinics may set their own guidelines, and these are summarized
in Table 9. Accordingly, there are substantial national
differences in the number of embryos transferred and the
proportions of multiple pregnancies. As might be expected,
countries with few or no regulations have a high proportion of
multiple births, generally as a result of transferring a high
number of embryos.
Table 8. Estimated excess costs attributed to multiple births per 10,000 births
following ovulation induction treatment.
Treatment Excess cost
(US$ million)
Twins Triplets
Clomiphene citrate 31.2 7.2
Gonadotrophins 17.3 12.0
ART 26.0 12.0
Total 74.5 31.1
524 ART = assisted reproductive technologies.
The USA perspective
Although there is no national legislation concerning the practice
of ART in the USA, guidelines are provided by the American
Society of Reproductive Medicine (ASRM) and its predecessor,
the American Fertility Society, in the form of reports by ethics
and practice committees. The most recent guidelines, which date
from November 1999 (ASRM Practice Committee, 1999),
provide the recommendations for pre-embryo transfer according
to the womans prognosis (Table 10). Despite the availability of
such guidelines, however, the total number of multiple births has
increased each year from 1980 to 2001 (Martin et al., 2002).
Although the percentage increase in multiple births varied on a
year-by-year basis, the rate of triplet births remained similar
from 1999 to 2001.
The clinical outcome report system of SART generates data
from all births associated with ART, but not those associated
with OI/OE. For the period 19971999, ART accounted for
0.7% of all births in the USA, including 0.3% of all singletons,
11.5% of all twins and 47% of all other multiple births
(Reynolds et al., 2003b). Nevertheless, during this period, there
was a downward trend in the number of triplets or higher-order
multiple births. The guidelines issued by ASRM in 1999 may
have helped reduce the number of triplet births over the past few
years. Furthermore, the increase in twins and the decrease in
triplets and higher-order births may be associated with fetal
reduction, which is not tabulated. In addition to this, there has
been much public debate in the USA about the problem of
multiple pregnancies. Nevertheless, the proportion of neonates
associated with multiple births has continued to rise annually,
and it is unknown whether regulatory action, rather than
guidelines, would help to reduce the incidence of multiple birth.
IVF success rates the importance of
data presentation
A Templeton
The data relating to infertility treatments and their outcomes
may be integrated into statutory regulations or national
guidelines. Individual centres make available their own results
for future patients, the media and national authorities
responsible for auditing and upholding standards. It is
important, therefore, that such data are published in a
consistent manner that allows clear messages to be presented.
Although both IVF and OI/OE with gonadotrophins followed
by IUI are widely accepted forms of infertility treatment, the
Proportion of
of overall costs (%)
Total
38.4 36.4
29.3 27.7
38.0 36.0
105.6
 Infertility therapy-associated multiple births

Table 9. Summary of policies for the prevention of multiple pregnancies in Europe. Data collated from questionnaires sent to
physicians within each country, January 2003. The table is based on one response per country.

Country Law on Official Official No laws/ Max no. Penalties Legal

ART regulation consensus regulations embryos changes
transferred expected?

Belgium <35a: 1 on 1st None No

attempt; 12
max on 2nd;
3539a: 2 on 1st
or 2nd attempt;
3 max thereafter
Czech (Society) 3 None
Republic
Denmarkc
Finland 50%:1b; None 2003
mean = 1.8
France No maximum None 2003
Germany 3 Prison
Greece No maximum
Hungaryc
Ireland No response Possibly
Italy 2 2003
The (Society) 2
Netherlands
Norway 2 in most cases 2003
Polandc
Portugal No maximum
Slovenia No maximum
Spain No maximum None
Sweden 2 Clinic loses 2003
(Central Board) licence
Switzerland 3 Prison
UK 2 (unless Clinic closed
exceptional
circumstances)
Ukraine More than 4 0 Possibly

ART = assisted reproductive technologies.

aMaternal age in years.
bIn 50% of cases, one embryo was transferred.
cNo data available.

Table 10. USA guidelines for pre-embryo transfer according
to maternal prognosis (ASRM Practice Committee, 1999).
Women with the most favourable prognosis (age <35 years,
good pre-embryo quality with adequate numbers for
cryopreservation): no more than two to be transferred
Women with above average prognosis (age <35 years but
without adequate numbers for cryopreservation): no more than
three to be transferred
Women with average prognosis (age between 35 and 40
years): no more than four to be transferred
Women with below average prognosis (age 40 years or with
multiple cycle failures): no more than five to be transferred
effectiveness of such techniques has not always been evaluated
rigorously. Published studies differ from national databases in
their reports of clinical outcomes and adverse events, and
neither report live birth rates per woman or couple treated.
Furthermore, many infertility clinics are concerned that
publication of crude data on live birth rates may reflect
negatively on those clinics with a high proportion of difficult-
to-treat women.
Many factors are known to influence the possibility of a
successful outcome following IVF treatment. The most
important factor is patient age, with younger women having a
greater chance of a successful outcome than older women
(Templeton et al., 1996). As a result, in both the UK and the
USA, success rates for infertility treatment are broken down
according to maternal age. Additional factors that influence
treatment outcome are the duration of infertility, previous IVF 525
 Infertility therapy-associated multiple births
treatment and previous pregnancy, particularly a live birth, all
of which need to be reported. Also required is a clear definition
of a cycle of treatment, and this should be applied consistently
to enable viable comparisons between centres. Although the
Human Fertilisation and Embryo Authority (HFEA) in the UK
reports abandoned treatment cycle rates, and the CDC in the
USA reports cancellation rates, these data vary substantially
between clinics between 4 and 35% in the UK, for example
(HFEA, 2002). As a result, concern has arisen about the
apparent impact on outcomes of a low abandonment rate; for
example, it is possible that a low abandonment rate may arise
from women being converted to other, non-reportable
treatments, and thus resulting in an apparent high success rate
for the individual clinic.
The number of embryos transferred during treatment
influences the likelihood of an individual patient becoming
pregnant, but it is now recognized that the number of embryos
available for transfer is also important. Success rates are
higher if embryos can be selected from a large pool rather than
from only one or two available embryos (Templeton and
Morris, 1998; ESHRE Campus Course Report, 2001).
Analysis of the HFEA database demonstrated no difference in
outcomes between transfer of two or three embryos, in cases
where four or more embryos were available. This applied in all
age groups up to 40 years (Templeton and Morris, 1998), and
results are now reported routinely in this way. Similar results
have also been reported from an analysis of the USA database
(Lynch et al., 2001). In cycles where cryopreservation was
performed, indicating a high number of good-quality embryos,
the maximum live birth rate was achieved in women below 35
years of age where two embryos were transferred. In women
aged between 35 and 40 years, there was a trend towards a
higher live birth rate in those in whom three embryos had been
transferred compared with those who had received two
embryos. In addition, detailed analysis of all UK clinics
indicated that elective two-embryo transfer was more likely to
achieve a singleton birth and avoid triplets without
compromising the overall success rate (Ozturk and Templeton,
2002).
Evidence suggests that where there is adequate provision of
health insurance cover or state funding, there has been a swift
move towards reducing the number of embryos transferred,
decreasing the risk of multiple pregnancies. Analysis by the
author (Templeton) of data provided by IVF clinics in the UK
has indicated that those wholly or mainly in the private sector
are associated with higher multiple pregnancy rates, lower
two-embryo transfer rates and average success rates compared
with those based in or associated with the public health sector.
Insurance issues remain confusing in the USA. It has been
found that some states within the USA with mandatory health
insurance for IVF transfer fewer embryos and have a higher
utilization rate of services compared with those that do not
require insurance cover (Jain et al., 2002). However, a
subsequent study comparing the same three states with three
matched non-insurance states found that only two of the states
with insurance coverage had a lower proportion of higher-
order (3) embryo transfers, and only one had a significantly
lower rate of multiple births (Reynolds et al., 2003b).
It is generally accepted that reporting the outcomes data for
526 individual IVF clinics is important for providing patient
information, transparency of procedures and clinical audit.
However, there is little consistency between centres in the
current reporting of these data, and improved methods of
reporting are therefore required. This includes information
about the rates of transfer of one or two embryos, multiple
gestation rates, and twin and triplet births. A move towards
reporting the cumulative live birth rates per woman or couple
based on each egg recovery should also be considered. By
replacing fewer embryos more often, reports should take into
account both fresh and subsequent cryopreserved embryo
transfers (Templeton, 2000; Ozturk et al., 2001), although it
should be noted that the feasibility of such reports has been
questioned due to the time that might elapse between first egg
retrieval and final embryo transfer. However, further studies
are required in all age groups to assess the cumulative success
rate for one-embryo replacement compared with two-embryo
replacement success rates, when each results from a single egg
recovery procedure. Similarly, the best strategy of embryo
replacement needs to be established in cases where three
consecutive egg recovery procedures are planned. Finally,
changing the definition of success rate from the live birth rate
per individual embryo transferred to the live birth rate per
woman at the end of a course of treatment, may ensure a move
towards a more meaningful understanding of success in
infertility therapy.
The responsibility of the fertility specialist
in preventing multiple pregnancies in ART
F Shenfield
If the goal of infertility treatments is a singleton pregnancy,
multiple gestations should be viewed as complications rather
than a desirable outcome. As with any medical intervention,
the physician has a responsibility to minimize the potential for
adverse events, i.e. multiple gestations in the case of infertility
treatments. In addition, there is a moral responsibility to
reduce the risk of harm to the unborn infant that might
otherwise result from a twin or higher-order multiple
pregnancy.
The ethical dilemma for the infertility practitioner is to create
a balance between the desire to maximize the opportunity for
the infertile couple to have a child and the need to minimize
the risk of harm to the future child and the family. The ability
of parents to make a rational decision about the number of
embryos to be replaced is often impaired by their desire to
have a child, by the financial pressures created through
restricted access to public funding of infertility treatment, by
their unrealistic appraisal of the potential risks and by their
wish to decide how many children they want in their family.
Hence, it is the physicians responsibility to inform parents
fully about the appropriate treatment for individual cases and
the risks associated with multiple pregnancies, minimizing the
potential for conflict, for example about the number of
embryos to transfer. Thus, the physician should act with
responsibility to the potential child rather than through a
paternalistic attitude towards the potential parents.
A similar principle applies when prevention of multiple
pregnancy has been unsuccessful and there may be a need to
consider reduction of a pregnancy. Patients who become
pregnant after a long period of infertility often attribute a high

value to the embryos, the fetuses and the pregnancy itself.
Nevertheless, for high-order multiple pregnancies in
particular, the benefits of reduction exceed the disadvantages
of carrying the pregnancy to term or risking a miscarriage
(Boulot et al., 1993; Lipitz et al., 1994). The aim of MPR is to
act with responsibility towards potential children by increasing
the chance of development of the remaining fetuses.
Physicians also have a political responsibility to inform policy-
makers about the most appropriate infertility treatments.
Without equal or fair access to public funding for infertility
treatment, the pressure is increased both on the parents and on
the physician to maximize the chances of a live birth with the
potential to ignore the consequences of multiple pregnancies.
Public funding for a specified number of cycles that would
give patients a chance of a healthy singleton birth would
minimize these pressures. Additionally, policy-makers should
be aware of the consequences of multiple pregnancies and the
potential cost-effectiveness of infertility treatment aiming at a
singleton pregnancy.
Infertility practitioners have important professional and moral
obligations to the potential parent, their potential offspring and
to society. They should lead the way in advising on the most
appropriate techniques, such as reduction in the number of
embryos replaced, both to patients and national policy boards
in order to optimize clinical practice and so benefit all those
involved.
Discussion
Much of the discussion focused on whether or not it is
appropriate to develop laws specific to the issues surrounding
multiple gestation and infertility therapy. Although a
unanimous view was not reached, it was agreed that self-
regulation has not been shown to work so far due both to
differences in ethical and scientific viewpoints, and also to a
lack of evidence-based data. Self-regulation works best where
methods are defined clearly, and yet current infertility
guidelines are based on assumptions rather than evidence from
well-designed clinical studies. The alternatives to self-
regulation are either the use of guidelines, with sanctions
imposed, for example by the medical profession against those
clinics that fail to abide by their recommendations, or the
development of specific laws. Both options have advantages
and disadvantages, but opinions on the best approach varied
because of country-specific issues and attitudes. For example,
regulations are highly respected in the UK and clinicians
generally adhere to them, whereas guidelines based on
scientific data have been produced in USA, but clinicians
cannot be sued if they do not follow practice according to their
patients needs.
Currently, OI/OE procedures are not included within the
definition of ART. However, it was recognized that this often
complicated the arguments and issues regarding measures to
reduce multiple pregnancies, and it was suggested that the
definition of ART be broadened to include these techniques.
There was general agreement that infertility physicians have a
number of responsibilities towards their patients, the
healthcare system and also society. Firstly, avoidance of
multiple pregnancies is a key priority. These should be
Infertility therapy-associated multiple births
recognized and reported as a complication of IVF or OI/OE.
The use of low-dose drug protocols to reduce multiple follicle
development or switching patients undergoing OI/OE to IVF
protocols is one means of potentially reducing multiple
gestations in women undergoing ovulation induction
procedures. However, there exists no unanimity of opinion on
this matter, as some would argue that ovulation induction
procedures, by their very nature, will result in multiple
ovulations and, therefore, multiple gestations. Thus, ovulation
induction cannot be modified in a way to render it less
problematic in terms of the genesis of high-order multiple
gestations. Studies are also required to assess different
approaches to embryo transfer. In particular, it needs to be
established whether transferring individual embryos on several
occasions which increases the likelihood of the uterus being
receptive during one of these instances or transferring
several embryos on one occasion is most likely to provide the
best chance of a successful outcome. Education of physicians
is also essential to the development of optimal practice, and it
was suggested that OI/OE should only be performed by
appropriately trained practitioners with adequate facilities.
According to some, such may not be sufficient in that the very
nature of OI/OE precludes these procedures from being
associated with acceptable multiple gestation rates.
Although collection of data relating to the various aspects of
infertility treatment allows comparison between clinics,
differences may occur through incorrect reporting or through
differences in data collection methods. There was general
agreement that live birth rate per woman treated was a more
useful definition of the effectiveness of a technique than birth
rate per single intervention, such as embryo transfer. However,
it was difficult to envisage how this might be implemented
within the annual reporting procedures in some countries.
Finally, it was agreed that more data from a prospective
clinical trial are required to determine the costs associated with
SET or dual-embryo transfer (DET), and also with singleton
and multiple births. It is important to obtain data relating to
costs both before and after birth.
Prevention of multiple gestation
attributable to IVF
By limiting the number of embryos transferred per stimulated
IVF cycle, the incidence of multiple gestations is reduced.
However, when following this policy, a number of
considerations are necessary in order to maintain an acceptable
pregnancy rate. When the number of embryos transferred per
cycle is limited to one or two, the prognosis of the patient and
the quality of embryos transferred are key to the success of the
procedure. Whereas the definition of a good prognosis patient
remains contentious, a number of scoring criteria have been
devised to predict embryo implantation rates upon transfer.
Furthermore, investigations into the transfer of embryos at
different developmental stages have shown that the decision of
whether to return an embryo at the pronuclear or blastocyst
stage also affects the pregnancy rate. Underpinning this
strategy of reducing the number of multiple births is an
efficient cryopreservation programme, which will maintain the
viability of supernumerary embryos. An interesting alternative
to this approach, which would also effectively eliminate
multiple births, is natural cycle IVF. 527
 Infertility therapy-associated multiple births
The utility of natural cycle IVF
J Gerris
Natural cycle IVF has been almost completely replaced by the
more effective technique of stimulated IVF/ICSI. Natural
cycle IVF is, however, a low-risk, low-cost and patient-
friendly procedure that may be suitable for some patients. The
advantages of this technique include almost no multiple
pregnancies, a zero risk of ovarian hyperstimulation syndrome
(OHSS), fewer interventions per cycle, and less physical and
emotional stress for patients when compared with stimulated
ovulation protocols.
Pelinck et al. (2002) have published a systematic literature
review that addresses the issue of effectiveness of natural
supported or mild stimulation protocols in IVF. It reviews 20
studies of natural cycle IVF: 12 case series and eight in which
a comparison was made between natural cycle IVF and IVF
with ovarian stimulation. While good-quality, randomized,
controlled trials and formal cost-effectiveness analyses are
lacking, the 20 selected studies comprised a total of 1800
cycles of natural cycle IVF, resulting in 819 embryo transfers
(45.5% per cycle) and 129 ongoing pregnancies (7.2% per
cycle and 15.8% per embryo transfer).
One of the problems associated with natural IVF is the number
of cancellations brought about by premature luteinizing
hormone (LH) rise. Some clinicians have, however, improved
the efficacy of this technique by using natural supported IVF,
in which the early LH surge is prevented by the use of a
gonadotrophin-releasing hormone (GnRH) antagonist. This
necessitates follicular growth to be supported by a small dose
of gonadotrophin, usually a recombinant follicle-stimulating
hormone (FSH). In vivo maturation (IVM) of oocytes is also
used with natural cycle IVF, and trials in patients with the
polycystic ovary syndrome (PCOS) have shown encouraging
results, suggesting PCOS may be an indication for this
technique. During one such trial, 20 patients were treated in 25
cycles with IVM and ICSI, resulting in eight clinical
pregnancies, of which two ended in miscarriage (Tan and
Child, 2002). IVM has also been advocated for patients with
poor oocyte yield after gonadotrophin stimulation, patients
with non-putative high competence (PHC) embryos after IVF,
or potential oocyte donors with polycystic ovaries.
The role of natural cycle IVF in the treatment of infertility will
become clearer once more data are available from randomized,
controlled trials. One such trial is currently underway in the
Netherlands. The outcome of a regular stimulated IVF cycle is
being compared with the cumulative outcome of three natural
IVF cycles, with data on health-economic measures and
patient satisfaction being assessed as secondary endpoints.
Individualization of the number of
embryos transferred
A Van Steirteghem, J Gerris and R Frydman
Although the aim in IVF/ICSI treatments is to optimize the
chance of a singleton live birth, the transfer of only one
embryo must be limited to a selected patient population if the
528 overall pregnancy rate is to be maintained. Strategies are
therefore being developed to identify patients for whom SET
is a feasible option.
One of the strongest predictive factors for birth and multiple
birth is the age of the mother, with pregnancy rates decreasing
with age, particularly after 38 years. The type of infertility
problem also plays a role, as couples affected by male factor
infertility have a higher pregnancy rate compared with those in
which a female factor is the cause of infertility. Other correlating
factors, such as FSH dose and tubal infertility, however, have
odds ratios which are generally close to one, suggesting a low
impact of these variables on pregnancy rates. Perhaps the most
successful indicator of multiple births is, however, the quality
and likely implantation success of the embryos by IVF, and
great efforts have been made to identify the key features of high-
quality embryos. The benefits of these approaches have recently
been shown from the experience of several countries in which
the introduction of elective SET (eSET) has dramatically
reduced the twinning rate and completely eliminated the
incidence of higher-order multiple pregnancies, without causing
a decrease in the overall pregnancy rate (OPR) (Vilska et al.,
1999; Gerris et al., 1999, 2002; Martikainen et al., 2001;
Tiitinen et al., 2001; De Sutter et al., 2003).
The elective transfer of one PHC embryo
Gerris et al. (1999, 2002) have shown that the elective transfer
of one embryo was consistent with an acceptable OPR when a
PHC or top-quality embryo was available for transfer. PHC
embryos were defined as having an absence of multinucleated
blastomeres, the presence of four or five blastomeres on day 2,
a minimum of seven cells on day 3, and a maximum of 20%
anucleated fragments (Van Royen et al., 2001).
The feasibility of eSET was initially demonstrated by
retrospectively judging the quality of embryos that had been
transferred in DET procedures. In total, 106 transfers of two
PHC embryos resulted in 65 (61%) ongoing pregnancies with
37 (57%) twins, while 65 transfers of one PHC embryo and one
non-PHC embryo resulted in 38 (58%) pregnancies with eight
(21%) twins, and 52 transfers of two non-PHC embryos resulted
in 12 (23%) pregnancies and no twins (Van Royen et al., 2001).
Comparative efficacy of SET and DET
The relative efficacies of SET and DET have been compared
in two prospective studies of patients undertaking their first
IVF/ICSI cycle. In the first study, patients >34 years of age
with >2 PHC embryos available for transfer were randomized
to DET or SET. The OPR with SET was acceptable at 39%,
compared with 67% with DET (Gerris et al., 1999). During the
second study, patients >38 years of age chose between SET or
DET of their two best embryos. If SET was chosen but no PHC
was available, DET of the two best embryos was performed.
From a total of 367 transfers, 186 (51%) resulted in
conception, and there were 148 (40%) ongoing pregnancies
and 136 (37%) live births. Both DET (65/161) and SET
(83/206) gave OPR of 40%. There were no twins following
SET compared with 18 ongoing twin pregnancies in the DET
group, resulting in 15 live births. This study also assessed the
total costs for care of the mother and child incurred up to 3
months after delivery. The significantly higher costs for the
DET group (US$8868 1469) compared with the SET group
 Infertility therapy-associated multiple births

(US$4537 375; P = 0.006) were wholly attributable to the
twin pregnancies (Gerris et al., unpublished).
In addition to the patients enrolled in the studies detailed
above, a number of patients who did not fulfil the criteria for
either study elected to undergo SET. The outcomes from DET
and SET in all selected and unselected patients are shown in
Table 11. From these data, it has been estimated that if the
ability to select PHC embryos had been used to maximize
pregnancy rates by transferring two PHC embryos, rather than
by the use of eSET, the OPR would have approached 45%.
Through eSET, stable pregnancy rates were maintained, while
the chances for a singleton live birth were optimized. Over the
5-year period of these studies, the multiple pregnancy rate
decreased from 33% in 1998 to only 12% in 2002, while the
ongoing implantation rates and ongoing pregnancy rates
remained stable at about 21% and 31%, respectively.
The elective transfer of three embryos
When no PHC embryos are available, reducing the number of
embryos transferred from three to two is associated with a
lower pregnancy rate (Tasdemir et al., 1995). However, several
studies have shown that avoiding triplets by transferring only
two embryos should not necessarily be accompanied by a
reduction in the pregnancy rate, if good-quality embryos are
available (Table 12) (Waterstone et al., 1991; Nijs et al., 1993;
Staessen et al., 1993, 1995; Tasdemir et al., 1995; Milki et al.,
1999; Ludwig et al., 2000; Licciardi et al., 2001).
Role of blastocyst transfer
D Gardner
The success of embryo transfer may be improved by
prolonging the in-vitro culture period from the pronuclear to

Table 11. Outcomes from SET and DET with PHC or non-PHC embryos in unselected IVF/ICSI patients.

All patients ages (n) SET with SET with DET with DET with DET without
PHC non-PHC two PHC one PHC PHC

Transfers 461 117 341 236 456

Conceptions 244 (53) 35 (30) 218 (64) 134 (57) 147 (32)
Ongoing pregnancies 174 (38) 24 (21) 169 (50) 97 (41) 97 (21)
Singletonsa 172 (99) 23 (96) 97 (57) 65 (67) 78 (80)
Twinsa 2 (1) 1 (4) 67 (40) 32 (33) 19 (20)
Dizygotic tripletsa 0 0 5 (3) 0 0

Values in parentheses are percentages.

aOngoing pregnancies (%).
DET = dual-embryo transfer; ICSI = intracytoplasmic sperm injection; IVF = in-vitro fertilization; PHC = putative high competence;
SET = single-embryo transfer.

Table 12. Pregnancy rates and higher-order pregnancy rates after elective transfer
of two or three embryos.

Pregnancy rate High-order pregnancy

(%) rate (%)

No. of 2 3 2 3
embryos
transferred

Waterstone 72/202 (36) 31/96 (32) 0/62 (0) 1/27 (4)

et al. (1991)
Staessen 34/80 (43) 50/103 (49) 0/34 (0) 9/50 (18
et al. (1993)
Nijs et al. 168/487 (34) 53/165 (32) 0/168 (0) 6/53 (11)
(1993)
Staessen 92/43 (21) 163/899 (18) 1/92 (1.1) 19/163 (12)
et al. (1995)
Tasdemir 17/42 (41) 30/70 (43) 0/17 (0) 3/30 (105)
et al. (1995)
Ludwig 31/123 (25) 313/1095 (29) 0/31 (0) 9/313 (3)
et al. (2000)
Miki et al. 22/29 (76) 18/24 (75) 0/22 (0) 4/18 (29)
(1999)
Licciardi 42/73 (58) 210/376 (56) 0/42(0) 29/210 (14)
et al. (2001) 529
 Infertility therapy-associated multiple births
the blastocyst stage, thereby allowing better assessment of the
embryos viability. Thus, whereas there have been no reports
of implantation rates above 28% when pronucleate embryos
are transferred, or no reports of implantation rates greater than
50% with the transfer of cleavage-stage embryos, implantation
rates of up to 70% are possible following transfer of day 5
embryos (Figure 2) (Gardner and Lane, 2003). Prior to
blastocyst formation, the maternalembryonic genome
transition is not complete. The cleavage-stage embryo is
essentially a cleaving oocyte, cleaving under the control of
proteins and messenger ribonucleic acid synthesized during
oocyte maturation. Therefore, cytoplasmic deficiencies and
chromatin damage in either the oocyte or sperm may not be
apparent prior to compaction.
The uterine environment is also better able to meet the
nutritional requirements of a blastocyst than a pronuclear or
cleavage-stage embryo. Embryos on day 13 may have
diminished viability through exposure to metabolic stresses,
caused by being in the wrong region of the reproductive tract
(the uterus) during development. Minimization of premature
exposure of the embryo to the uterine environment through
blastocyst culture may be particularly beneficial in women
who have undergone ovulation induction, in whom the uterus
may be sub-optimal for implantation. Furthermore, as uterine
contractions decrease over time following human chorionic
gonadotrophin (HCG) administration, it is probable that in
transferring the embryo at the blastocyst stage, there is less
chance of the embryo being expelled from the uterus (Fanchin
et al., 2001).
The majority of clinical studies have shown higher success
rates with day 5 than with day 3 embryos. Thus, of the nine
prospective, randomized trials of blastocyst transfer, five trials
found that transfer on day 5 was superior to transfer on day 3,
whereas three trials found the same outcome with embryos of
both ages and one trial concluded that day 3 was superior to
day 5 (Gardner and Lane, 2003; Gardner et al., 2003). A
disadvantage of blastocyst transfer is, however, that there will
be a small increase in the number of patients who do not have
an embryo available for transfer.
In a prospective, randomized trial comparing the transfer of
one or two blastocysts in a group of good prognosis patients, it
was determined that an ongoing pregnancy rate of 60.9%
Figure 2. Maximum published implantation rates following
the transfer of human embryos to the uterus on either day 1, 3
530 or 5 of development (Gardner and Lane, 2003).
could be established with the transfer of single blastocysts with
no twin pregnancies (Gardner et al., 2003).
Efficacy of embryo scoring and screening
L Gianaroli
The selection of embryos for transfer is one of the most
difficult aspects of reproductive medicine. Several criteria can
be used to identify the best embryos, and it is likely that the use
of a combination of various scoring criteria throughout pre-
implantation development will lead to higher chances of
identifying the most viable embryo for transfer.
Pronuclear morphology
Alterations to any of the strictly regulated events of pronuclei
alignment, syngamy or fusion may cause abnormalities in
embryo division that can be observed as uneven cleavage or
fragmentation. Thus, the different patterns observed in the
morphology of pronuclear zygotes can be used to score
embryo viability (Figure 3) (Tesarik and Greco, 1999; Magli
et al., 2001).
Embryo development rate
The rate of embryo development may give an indication of
embryo quality, and early entry into the first division from
zygote to two-cell embryo has been associated with increased
implantation potential (Shoukir et al., 1997; Magli et al., 2001)
(Figure 4). Chromosomal analysis of day 3 embryos has
shown that the rate of cleavage is strictly related to the rate of
aneuploidy (Magli et al., 2001), while it appears that an
abnormal cleavage rate is associated mainly with
chromosomal abnormalities.
Fragmentation
Fragmentation is also associated with chromosomal
abnormalities, and the lowest incidence of such abnormalities
is observed in embryos without fragmentation (Magli et al.,
2001) (Figure 5). However, the presence of small fragments
does not affect embryo development to the same extent as
large fragments, which may deplete organelles or micronuclei
from the embryo.
Figure 3. Percentage of embryos with a normal chromosomal
complement (light grey line), monosomies or trisomies (dotted
line) or complex abnormalities (solid black line), in relation to
the configurations of pronuclear zygote morphology (Magli et
al., 2001).

Blastomere multinucleation
Multinucleated blastomeres are frequently observed in day 2
embryos, especially in two-cell embryos, suggesting that a
considerable number of human embryos become abnormal
during the first division. Approximately 30% of arrested
embryos are found to be multinucleated. If multinucleated
embryos do implant, a high proportion carry complex
chromosomal abnormalities (Magli et al., 2001).
Development to blastocyst
Euploid embryos grow to the blastocyst stage at a higher rate
than chromosomally abnormal embryos (Figure 6). However,
development to blastocyst is not in itself an indication of a
PHC embryo, as 26% of abnormal embryos develop to the
blastocyst stage (Magli et al., 2001).
Preimplantation genetic diagnosis
Assessment of the chromosomal constitution can be used to
assess the implantation potential of the embryo. It has been
suggested that the use of pre-implantation genetic diagnosis
(PGD) for aneuploidy might help to reduce the incidence of
early abortions (Gianaroli et al., 1999; Munn et al., 1999).
Figure 4. Distribution of chromosomally abnormal embryos
(in black the proportion due to monosomy and trisomy)
according to the cleavage stage at 62 h post-insemination
(Magli et al., 2001).
Figure 5. Distribution of chromosomally abnormal embryos (in
black the proportion due to monosomy and trisomy) according
to the percentage of fragmentation (Magli et al., 2001).
Infertility therapy-associated multiple births
The role of cryopreservation programmes
L Veeck and Z Rosenwaks
Irrespective of the implantation rate achieved with fresh
blastocyst transfer, the SET and DET procedures would not be
valid if it were not possible to successfully cryopreserve the
remaining blastocysts to maximize the possibility of pregnancy
from a single IVF procedure. With effective cryopreservation, a
higher pregnancy rate and a lower multiple gestation rate can be
achieved. Outcomes are significantly enhanced when the
cumulative effect of adding pregnancies resulting from the use
of thawed pre-embryos (only from cycles failing to become
pregnant after fresh transfer) to cycles using fresh pre-embryos
is examined. At least in some programmes, the probability of
pregnancy following transfer of a thawed pre-embryo is nearly
equal to that resulting from transfer of fresh pre-embryos.
Methods of cryopreservation and replacement
Most pre-embryo freezing protocols make use of 1,2
propanediol or dimethylsulphoxide as cryoprotectants (Testart et
al., 1986), whereas glycerol and sucrose are generally used in
blastocyst-freezing protocols (Mnzo et al., 1993). Regardless
of the stage of pre-embryo development, the concentration of
cryoprotectant is increased step-wise before freezing and
decreased step-wise after thawing.
Although not all blastomeres survive the rigors of freezing and
thawing, dying blastomeres may be removed by aspiration
through an artificial hole in the zona pellucida, and therefore the
loss of a few blastomeres during freezing will not compromise
the viability of the entire specimen. Thus, the many cells of the
blastocyst provide an added advantage in the freezethaw
process compared with the pre-embryo. Thawed conceptuses
may be replaced in either natural or programmed ovulation
cycles.
Natural cycle replacement is followed in patients with normal
endogenous concentrations of luteal phase progesterone during
their ovulatory cycles. Supplementary progesterone is
administered only if medically indicated, or if a previous
pregnancy failed under a non-supplemented protocol.
Figure 6. Rate of blastocyst formation according to the
cellular stage in embryos with a normal (straight line) or
abnormal (dotted line) chromosomal complement (Magli et
al., 2001). 531
 Infertility therapy-associated multiple births
Pre-embryos are thawed and transferred 1 day after ovulation,
whereas blastocysts are thawed either 4 days after the LH peak
and transferred the following day (day 5 blastocysts), or are
thawed and transferred 5 days after the LH peak (day 6
blastocysts). During programmed cycle replacement, a GnRH
agonist provides luteal suppression from day 1 to day 15 of the
cycle, oestrogen is provided by transdermal patches in
increasing concentrations for the first 7 weeks, and
progesterone is given from week 3 to week 12 of gestation.
Pre-embryos are thawed and transferred on day 17, whereas
blastocysts are either thawed on day 19 and transferred on day
20 (day 5 blastocysts), or are thawed and transferred on day 20
(day 6 blastocysts).
Pregnancy success rates
Studies performed at Cornell University have shown that
transferring cryopreserved blastocysts results in a higher
clinical pregnancy rate compared with cryopreserved pre-
embryos (Table 13). No differences were apparent in
pregnancy rates between natural or programmed replacement
cycles, or with maternal age, although women >40 years of age
had almost double the miscarriage rate of younger women.
Furthermore, there was no difference between the ongoing
pregnancy rates obtained with day 5 or day 6 frozenthawed
blastocysts, suggesting that the rate of blastocyst development
may not be crucial to subsequent post-thaw success (Behr et
al., 2002). This is in contrast to previous reports of fresh
transfer (Shapiro et al., 2001) and cryopreservation (Marek et
al., 2000), in which pregnancy rates were found to be lower
with the slower growing conceptuses.
The role of cryopreservation programmes
M Germond
The legal constraints imposed on cryopreservation in Germany
and Switzerland provide an environment in which the success
of freezing at the two pronuclear stage can be assessed
(Germond and Senn, 1999). In these countries,
cryopreservation after syngamy and the in-vitro development
of more than three embryos is forbidden. Germond and Senn
(1999) showed that pronuclear zygotes, which had been
cryopreserved under this programme and cultured for an
additional 2448 h after thawing, had implantation rates
similar to those of fresh embryos with the same morphological
characteristics, which had also been replaced in unstimulated
cycles. When all homogenous transfers and all total transfers
were compared, however, fresh embryos were found to result
in higher implantation rates than the frozen embryos (Table
Table 13. Embryo survival, pregnancy and implantation rates
by stage of development of the transferred conceptus.
Pre-embryos (%) Blastocysts (%)
Survived/thawed 1841/2359 (78.0) 327/424 (77.1)
Clinical pregnancy/ 160/425 (37.6) 82/138 (59.4)
transfer
Sacs/transferred 242/1582 (15.3) 111/294 (37.8)
Pre-embryos frozen January 1995 to December 2002;
532 blastocysts frozen July 2000 to December 2002.
14). Furthermore, fewer embryos that had been cryopreserved
reached the 4-cell stage (42%) compared with fresh embryos
(57%; P = 0.001), and the occurrence of heavy fragmentation
was also more frequent among cryopreserved embryos (15%
versus 13%; P = 0.002) (Germond and Senn, 1999). Despite
the reduced efficacy compared with fresh embryo transfer, this
policy has not been detrimental in terms of global treatment
outcome. The maximum number of fresh embryos transferred
has decreased from three to two, which has decreased multiple
births while maintaining the cumulative delivery rate per
oocyte collection (32% versus 34%).
Discussion
The key issue is whether it is ever acceptable to risk the
prospect of multiple births by transferring more than one
embryo and, if so, what should influence the decision to
transfer one, two or three embryos. Although the suggestion
that SET should apply to all patients undergoing IVF was
vigorously discussed, this approach was not widely accepted.
Instead, an initial strategy was proposed that might potentially
halve the number of multiple births without unduly harming
the overall pregnancy rate. Thus, it was suggested that SET
should be applied to all good prognosis patients or,
alternatively, to the first and second cycles of IVF in patients
<35 years of age. Only after such a strategy has been widely
adopted and the outcomes analysed scientifically should it be
recommended as a useful guideline. Perhaps then the more
difficult question of lowering the number of embryos
transferred to poor prognosis patients can be addressed.
Furthermore, it was suggested that a prospective, randomized
trial comparing outcomes following transfer on day 3 or day 5
thawed singleton transfers could help to evaluate the
usefulness of SET after cryopreservation thawing.
It was agreed that triple-embryo transfer should be avoided in
most patients. Because of the overall consensus that transfer of
any more than two embryos poses a true risk for high-order
multiple births, it is important to maintain non-transferred
Table 14. Implantation rates (number of sacs/number of
transferred embryos) of fresh and cryopreserved embryos
according to the number of blastomeres and morphological
grading.
Fetal sacs/embryo transferred (%)
Number of Fresh cycles Cryopreserved cycles
blastomeres
(grades)
1 0/35 (0.0) 0/132 (0.0)
2 (I,II,III) 36/386 (9.3) 47/459 (10.2)
3 (I,II,III) 7/49 (14.3) 9/111 (8.1)
4 (I,II,III) 424/2196 (19.3)a 178/1160 (15.3)
24 (IV) 4/140 (2.9) 10/195 (5.1)
Total 471/2806 (16.8)b 244/2057 (11.9)
All transfers 844/6030 (14.0)b 481/4986 (9.6)
aP = 0.005; bP = 0.0001.
Oocyte collections between January 1993 and December 2000.
Cryopreservation at pronuclear stage. Homogeneous transfers on day 2 only,
including transfers in which all embryos were at exactly the same stage
of development.

embryo viability through effective cryopreservation
programmes, thus allowing further implantation attempts
without the need for OI/OE.
A central issue when deciding between SET and multiple
transfer the prognostic status of the patient was discussed
at length. The definition of a poor prognosis patient is,
however, contentious and a consensus of opinion was not
achieved. Indeed, it was decided that a further conference
would be necessary to fully formulate such a definition.
Nevertheless, there was general agreement that
embryo/blastocyst scoring should be used with poor prognosis
patients to help establish the quality of the embryo and the
putative implantation success.
Currently, the probability of successful implantation is judged
mainly according to embryo/blastocyst morphology, but the
addition of other markers, such as metabolic activity, might
improve the predictive value of the score. In addition, levels of
sperm chromatin damage and uterine receptivity markers may
also help determine implantation success. It was agreed that
culturing the embryo to the blastocyst stage is generally
beneficial, and that detection of chromosomal abnormalities
with PGD should theoretically increase the per cycle
likelihood of implantation. PGD was generally considered to
be valuable in specific patient groups, in whom the
cost/benefit ratio would be favourable, such as those with
recurrent abortions. There was widespread agreement over the
importance of assessing the predictive value of scoring
systems. Application of diagnostic test techniques, to assess
the robustness of predictions using statistical criteria, would
clarify the value of the scores and improve quality assurances.
Indeed, the need for high-quality assurance and control within
and between laboratories was a recurrent theme.
As embryo scoring is achievable only during incubation, it was
acknowledged that patients and physicians should decide the
limit for the number of embryos to be transferred beforehand.
Patient awareness and expectations were discussed at length,
and the need to educate patients to think in terms of singleton
pregnancy rates, rather than absolute pregnancy rates, was
emphasized. It was suggested that quality could be redefined
as implantation rate, or if this was too confusing for patients,
as the number of embryos needed to accomplish singleton
pregnancies. As patients are familiar with the precautionary
approach in other branches of medicine and science, it was
suggested that, with explanation, this approach could be well
accepted in IVF.
The risks entailed with multiple births were also discussed,
including the potential threat of litigation from children from
such births. Many participants agreed that their primary
responsibility was to do no harm and, with this in mind, that
the potential risks from multiple births were too high a price to
pay for combating childlessness.
Prevention of multiple gestations
attributable to ovulation induction
or ovulation enhancement
Interventions to induce or enhance ovulation provide the
opportunity for pregnancy and motherhood in women with
Infertility therapy-associated multiple births
ovulatory dysfunction, such as WHO Type I or Type II
anovulation, although such procedures also carry a risk of
promoting multiple gestations. However, this area has received
less attention than that of multiple gestations after IVF, despite
the fact that risks to the health of both the mother and the
fetuses and the associated costs are the same, regardless of the
therapy responsible for its cause. There is therefore a clear
need for measures to minimize the risks of multiple gestation
among women undergoing OI or OE, and this is an area where
close collaboration between infertility practitioners and the
pharmaceutical industry would be highly beneficial.
Ovulation induction and ovulation
enhancement as a risk factor for multiple
gestation
PN Barri
It is difficult to obtain a clear picture of the number of multiple
pregnancies that are attributable to OI/OE procedures, as there
is no system for recording the use of ovulation-inducing drugs
not associated with IVF procedures. Nevertheless, the
available evidence suggests that at least one-third of twin
pregnancies and the majority of triplet or high-order gestations
can be attributed to ovulation-induction procedures (Norwitz,
1998; Bergh et al., 1999b; Tur et al., 2001).
Based on an analysis of 1878 consecutive pregnancies resulting
from ovarian stimulation with gonadotrophins, Tur et al. (2001)
have demonstrated that patient age and the intensity of the
response to ovarian stimulation were key factors in determining
the risk of multiple pregnancy. Thus, patients aged 32 years
with more than three follicles >10 mm and oestradiol levels
>862 pg/mL on the day of HCG administration had a high risk
of experiencing a multiple pregnancy. Analysis of an additional
474 pregnancies further refined the criteria for an increased risk
of multiple pregnancy as patient age <35 years and the presence
of three or more follicles 14 mm. Conversely, statistical
analysis showed that patients over 38 years of age who did not
have at least two follicles 17 mm had a reduced probability of
becoming pregnant.
By applying a treatment algorithm based upon the criteria for
a high risk of multiple gestations (Figure 7), with cancellation
Figure 7. Treatment algorithm for reducing the risk of
multiple gestations in women undergoing ovulation induction
with gonadotrophins. E2 = oestradiol. 533
 Infertility therapy-associated multiple births
of those cycles in which there was an excessive response, it
was possible to reduce the rate of twin pregnancies to 11.6%
and that of triplet pregnancies to 2.5%.
The prevention of multiple gestation
attributable to OI and OE
P Devroey
In contrast to the situation regarding IVF, where many countries
now have guidelines or even legislation to restrict the number of
embryos transferred, and therefore the risk of multiple gestations,
no such guidelines have been developed with respect to OI/OE
plus IUI. Consequently, in an analysis of 220 patients referred for
MPR over three time periods (19861989, 19911992 and
19921993), Evans et al. (1995) found that whereas the number
and proportion of quintuplet and greater pregnancies resulting
from ART had fallen steadily, the incidence of such pregnancies
following OI remained steady.
Although some authors have found that there is a correlation
between oestradiol levels and multiple pregnancies in women
undergoing OI with gonadotrophins (Farhi et al., 1996; Valbuena
et al., 1996; Pasqualotto et al., 1999; Gleicher et al., 2000;
Dickey et al., 2001), other studies did not find such a relationship
(Kurachi et al., 1985; Dodson et al., 1988; Shelden et al., 1988;
Navot et al., 1991; Yu et al., 1991; Ben-Nun et al., 1993;
Goldenberg et al., 1994; Goldfarb et al., 1997). Similarly, the
predictive value of ultrasound monitoring for multiple pregnancy
occurrence has been shown in some (Navot et al., 1991; Farhi et
al., 1996; Valbuena et al., 1996; Gleicher et al., 2000; Dickey et
al., 2001), but not all reports (Kurachi et al., 1985; Dodson et al.,
1988; Shelden et al., 1988; Yu et al., 1991; Ben-Nun et al., 1993;
Goldenberg et al., 1994; Goldfarb et al., 1997; Pasqualotto et al.,
1999). Although these studies have not provided robust data on
which to base a reliable predictor of multiple gestations, they
may be used as a starting point for the design of prospective
predictive studies. At present there is a consensus in the positions
of SART (Grifo et al., 2001), ASRM (Soules et al., 2001) and the
Society for Reproductive Endocrinology and Infertility (SREI;
Paulson et al., 2001) that there are insufficient data upon which
to base practice guidelines for the avoidance of multiple
pregnancies following OI.
Despite the lack of specific guidelines to reduce the risk of
multiple gestations in women undergoing OI plus IUI, there are
a number of measures that may be employed to minimize these
risks. Firstly, agents other than gonadotrophins may be used to
induce ovulation in some women. For example, insulin-lowering
drugs such as metformin can restore ovulation patients with
PCOS, without exposing the patient to a risk of multiple
gestation, although robust data on pregnancy rates using this
approach are not yet available (Costello and Eden, 2003).
Similarly, dopamine agonists can restore normal ovulation in
women with hyperprolactinaemia, while pulsatile treatment with
GnRH can produce single ovulations in women with WHO type
I anovulation (Leyendecker and Wildt, 1983; Braat et al., 1991,
1992).
The guiding principle for the treatment of women with
anovulatory infertility should be restoration of the feedback
system that selects a single follicle for ovulation. The first-line
534 treatment for women with normogonadotrophic anovulation,
including those with PCOS, is CC (The ESHRE Capri Workshop
Group, 2000). The reported multiple pregnancy rate with CC
(mainly twins) ranges between 8 and 13% (Kolibianakis and
Devroey, 2002). Treatment with gonadotrophins should be
restricted to those women who are resistant to CC, as the risk of
multiple pregnancy is approximately 25% when these are
administered according to conventional step-up regimens
(Fauser and Van Heusden, 1997). Although the low-dose step-
up or step-down gonadotrophin are designed to maintain the
physiological principles of follicle selection and so are associated
with a high incidence of monovulation, they are associated with
slightly lower pregnancy rates than the conventional regimens
(White et al., 1996; Gleicher et al., 2000).
Cancellation of OI cycles by withholding HCG on the basis of
oestradiol levels or follicular number or size is an alternative
approach to the prevention of multiple gestations. Evidence from
retrospective studies suggests that if a cycle is cancelled when six
or more follicles 12 mm are observed by ultrasound, the
incidence of triplet pregnancies can be reduced by 67% (Dickey
et al., 2001). However, this approach will also lead to
cancellation of 33% of cycles and a reduction of 44% in
pregnancies achieved. It should also be borne in mind that
cancellation of cycles is frustrating for both patients and
physicians, and it wastes money and resources. An alternative
strategy is to convert OI/IUI cycles at high risk of producing
multiple pregnancies to an IVF procedure, thereby allowing
control of the number of embryos transferred (Antman et al.,
2002). The odds of successful conversion to IVF are increased by
the current availability of GnRH antagonists (Fatemi et al.,
2002). Nevertheless, a proportion of patients are unwilling to
proceed to IVF, and pre-ovulatory follicular reduction may be
employed in such cases. Aspiration of some follicles when more
than three follicles 15 mm were present on ultrasound, followed
immediately by HCG administration, has been shown to be
effective in producing singleton pregnancies (Albano et al.,
2001).
The role of the doctor
L Hamburger
The doctor has the most important role in the prevention of
multiple pregnancies in women undergoing OI. In the first
instance, it is important to ensure that the couple is fully informed
about all aspects of the procedure, including the potential risks of
OHSS and multiple gestations. The couple should be educated
that a singleton birth is the optimum outcome following OI, and
they must be prepared for the possibility that the cycle may need
to be cancelled or converted acutely to an IVF procedure, or that
follicular aspiration may be necessary if the woman displays
evidence of being at high risk for a multiple pregnancy. The
couple should also be asked about their views on multiple
pregnancy reduction, in the event that IUI results in a multiple
gestation. All these options and their implications must be
discussed with the couple before treatment with gonadotrophins
commences.
Patients who are planning to undergo OI/IUI require a more
careful work-up than patients scheduled for IVF prior to the start
of treatment. Detailed information is required about the patency
of the Fallopian tubes and the presence of any peri-ovarian
adhesions, in addition to information about the uterine cavity.
Even in cases where careful examination of the couple has

revealed no obvious impediments to conception with IUI in
stimulated cycles, the need to limit the number of such cycles
(ideally two) and proceed to IVF if pregnancy is not achieved
should be discussed.
Finally, it is important to recognize that doctors involved in the
management of infertile couples also have a political role, and
they should be fully involved in the generation and dissemination
of practice guidelines in the country in which they work. They
also need to alert politicians to the fact that multiple pregnancy is
not a cost-effective outcome to infertility treatment, and this is
even more evident in the case of high-order multiple pregnancy.
The doctor treating the infertile couple is better placed than
anyone else to explain the problems and pitfalls of infertility
treatment and work towards improved treatment regimes, with
the aim of improving outcomes and increasing the quality of life
of parents and offspring (Jones, 2003).
The role of the patient
J Carr
The infertile couple at the beginning of the twenty-first century
is typically able to gain unlimited access to literature providing
them with a surfeit of information about the various different
treatment options, statistics on success rates and anecdotal
stories of protocols resulting in pregnancy. However, they
focus on the ultimate outcome of the live birth of a child and
give little, if any, consideration to the potential for and possible
complications of higher-order pregnancies. Consequently, the
infertile couple arrives at the clinic with high expectations.
After the initial evaluation, it is essential that the doctor and
the infertile couple have a completely open and honest
dialogue about the potential risks of multiple births, and their
attendant financial, social, psychological and physiological
implications. The couple will often require some time to fully
appreciate the various ramifications of such an outcome before
proceeding with a course of treatment. However, it is
important to recognize that the couple may be so focused on
achieving a pregnancy that they are unable to identify with any
of the negative aspects of a multiple birth. Consequently, many
couples may decide that such complications can be addressed
on an if and when basis. They may also be reluctant to
question the doctors recommendations, due to fear that they
will be refused treatment if they appear to have any
uncertainties about the proposed protocol. Many patients
prefer to trust the doctor as the expert, to ensure that the
outcome will be desirable. Nevertheless, the policies and
practices of the clinic with regard to higher-order pregnancies
must be clearly and concisely explained to the patient, and
agreement must be reached upon the course of action to be
taken if complications arise, before any treatment is started.
Ultimately, the role of the infertile couple is largely determined
by their trust in the clinic to adhere to practices that offer safe
and socially responsible treatment options. Maintenance of
this principle should ensure the best possible outcome for the
patient.
Infertility therapy-associated multiple births
The role of the pharmaceutical industry
C Howles and GI Serour
Through the development and production of recombinant
gonadotrophin preparations and GnRH analogues and
antagonists, the pharmaceutical industry has undoubtedly
played a key role in the development of treatment strategies for
infertile couples over the past 20 years. It is appropriate,
therefore, that they should also be involved in the development
of strategies to address the problems of multiple gestations in
women who have received these drugs.
One important way in which the pharmaceutical industry can
contribute to a reduction in multiple gestations is through the
provision of clear and unbiased medical information for both
doctors and patients. Such information should promote the
delivery of a single healthy baby as the optimum outcome of all
ART procedures, while multiple births resulting from infertility
treatments should be presented as a failure not a triumph.
The pharmaceutical and biotechnology industries are already
contributing to an improvement in the outcomes of infertility
treatment by developing purer and more consistent
gonadotrophin preparations, as exemplified by the transition
from human urinary preparations to recombinant human
gonadotrophins. This has led to more convenient methods of
administration (s.c. versus i.m. injection; multiple dose versus
single injection forms), as well as improvements in the
efficacy, efficiency and safety of treatment, as demonstrated in
randomized, statistically powered clinical studies (Hedon et
al., 1995; Out et al., 1995; Recombinant Human FSH Study
Group, 1995; Bergh et al., 1997; Frydman et al., 2000; Lenton
et al., 2000; Schats et al., 2000). As all three human
gonadotrophins are now available as pure monotherapeutic
agents, it is possible to conduct research on their relative roles
during follicular development and so refine treatment
protocols for ovarian stimulation. This should lead in turn to
greater control of stimulation cycles and so help to reduce the
risk of multiple gestations. For example, the use of the chronic
low-dose, step-up protocol for FSH administration has been
shown to be associated with a multiple pregnancy rate of 5.7%
Figure 8. The LH ceiling concept (adapted from Balasch and
Fbregues, 2002). FSH = follicle-stimulating hormone; LH =
luteinizing hormone. 535
 Infertility therapy-associated multiple births

and an incidence of OHSS of <1% (Homburg and Howles,
1999). Similarly, studies are being performed to evaluate the
potential utility of the LH ceiling concept in promoting the
development of a single follicle. In essence, this concept,
which has been discussed in detail by Shoham (2002) and is
summarized in Figure 8, states that during follicular
development, LH concentrations should not exceed a ceiling
value (Hillier et al., 1995), and should not fall below a
threshold value (as demonstrated in studies on WHO I
anovulatory infertile women: Couzinet et al., 1988; Balasch et
al., 1995; The European Recombinant Human LH Study
Group, 1998). A feasibility study that utilized high daily doses
of recombinant human luteinizing hormone (r-hLH) to
evaluate the LH ceiling hypothesis in OI treatment regimens
compared the use of different doses of r-hLH or placebo
instead of FSH in the late follicular phase of stimulated cycles
in women with WHO type II anovulation concluded that r-
hLH alone could arrest multiple follicular growth whilst
supporting growth of a dominant follicle (Loumaye et al.,
2003). In addition, the availability of r-hLH has made it
possible to investigate the use of LH rather than HCG to
trigger final follicular maturation. A recent study has shown
that single doses of r-hLH (500030,000 IU) resulted in a
highly significant reduction in OHSS compared with urinary-
HCG, whilst the number of oocytes and pregnancies achieved
were similar (The European Recombinant Human LH Study
Group, 2001).
The HFEA can grant three types of licence: (i) a treatment
licence allows the unit to pursue treatments that fall under the
act, and encompasses all procedures that involve the use of
donated gametes, or embryos in-vitro (i.e. IVF and ICSI, but
not GIFT, IUI or OI); (ii) a storage licence allows
cryopreservation and storage of gametes and embryos; (iii) a
research licence allows specific research projects that use
human embryos in-vitro up to a maximum of 14 days.
The activities of all clinics carrying out ART procedures are
regulated by a code of practice, to which they must adhere in
order to receive and renew their licence(s). Renewable
licences are granted for periods of up to 3 years, but the unit is
subject to annual inspections and submission of annual reports
throughout the term of the licence. Each centre is obliged to
make a monthly return of all ART cycles (IVF, ICSI, frozen
replacements, etc), and failure to do so can jeopardize renewal
of the licence. Practicing without a licence is a criminal
offence that is punishable by a substantial fine and/or a
custodial sentence.
In common with the situation in the USA, the UK has seen a
marked increase in the incidence of multiple births (Figure 9),
particularly among older women probably the result of ovum
donation programmes (Figure 10). Although the figures do not
reveal the specific causes of this increase, as data relating to OI
procedures are not collected routinely, the HFEA database

Whilst recognizing the important contributions that the

pharmaceutical industry is making towards the refinement of
protocols for OI, it is incumbent upon them to ensure that they
publish not only the results of studies that are favourable for
their product, but to ensure that all relevant data are made
available. It is only with this information that physicians can
fully evaluate the relative advantages and disadvantages of the
various therapeutic options and so design treatment protocols
and formulate guidelines to maximize the chance of a
successful outcome to OI (i.e. a healthy singleton birth), and
minimize the risks of OHSS and multiple pregnancies.

The UK legislative experience: a model

for other countries?
P Braude Figure 9. Increasing incidence of multiple births in the UK.

The Human Fertilisation and Embryology Act was passed in

the UK in 1990 in response to the Report of the Committee of
Inquiry into Human Fertilisation and Embryology (the
Warnock Report; Warnock, 1985), which addressed three main
public concerns: (i) the creation and use in treatment of human
embryos outside the body; (ii) the use of these human embryos
in research; and (iii) the use of donated gametes and embryos.
This act required the establishment of the HFEA, which is a
statutory non-departmental public body that is accountable to
the Secretary of State for Health, and is responsible for the
licensing and regulation of all units in the UK that perform
ART procedures. It is composed of up to 24 members who are
appointed by the Secretary of State for Health, including a lay
chairman and deputy chairman. At least one-third, but not
more than half, of its membership may be registered medical
practitioners or those involved in assisted conception or its Figure 10. The increasing incidence of multiple births,
536 research funding. particularly among older women, in the UK.

reveals that IVF is responsible for a large number of multiple
gestations, particularly with respect to triplet births (HFEA,
2002).
In an attempt to minimize the risk of multiple gestations, the
first code of practice issued by the HFEA stated that no more
than three eggs or embryos should be replaced in a woman in
any one cycle. This has been strictly adhered to by all clinics,
as though it was a legally binding requirement, and it is a focus
of inspections and analyses of clinic returns. Nevertheless, this
policy was criticized in some quarters as an infringement of
the clinical freedom of the physician, and it was suggested that
practitioners should be allowed to use their judgment to
replace more than three embryos in certain patients, such as
women who were over 40 years of age or those with multiple
replacement failures. However, an attempt to challenge
implementation of this guideline through the courts in a
specific case in 1999 led to the position of the HFEA being
upheld.
More recently, data from both the HFEA and other countries
have led to revisions in the guidelines regarding embryo
transfer. Evidence has been presented that the elective transfer
of two embryos in cases where more than four embryos were
available resulted in a reduced number of triplets without
affecting the live-birth rate (Templeton and Morris, 1998), and
led to recommendations from the British Fertility Society and
the Royal College of Obstetricians and Gynaecologists to
transfer only two embryos. In line with these
recommendations, the HFEA produced revised guidelines in
August 2001, in which it was recommended that the number of
eggs or embryos normally to be transferred in any one cycle
should be reduced from three to two (HFEA Chairs Letter
Ch(01)10, 03/08/01 - HFEA Embryo Transfer Policy Review).
Although three embryos could still be transferred in
exceptional circumstances, the reasons for this decision must
be recorded in the patients records. However, analysis of the
HFEA register for 2000/2001 indicates that the guidelines are
not closely adhered to by all clinics, as 109 sets of triplets
(1.7%) and 1579 sets of twins (25%) were born from the
25,080 cycles undertaken. The range of two-embryo transfer
cycles varied substantially between in excess of 80% elective
transfer of two embryos (18 of the 64 centres) and less than
20% (four clinics) regardless of age. One-third of the centres
(21/64) accounted for 53% of the live-born triplets and more
than 50% of their transfers were with three embryos.
Future approaches to reducing the incidence of multiple
pregnancies could include ensuring that a clinics live-born
triplet rate is maintained below 1%, enforcing an upper limit of
two embryos to be transferred if this was exceeded (although
this would still lead to a large number of twin births), or
reducing the transfer rate to single embryos (with added cycles
by frozen embryo replacement). Both approaches are
measurable and thus enforceable, but the latter would achieve
the aim of almost abolishing multiple pregnancies derived
following IVF/ICSI. However, they limit clinical freedom and
patient choice, and might disadvantage older patients. Single
blastocyst replacement might be an alternative approach to
improve results from SET, with an endpoint of singleton
pregnancies per stimulation cycle.
Options for pursuing these types of changes include a change
Infertility therapy-associated multiple births
in primary legislation (which would be a lengthy and complex
procedure), recommendations/professional guidelines or a
change to the HFEA Code of Practice. The latter option would
be enforceable as part of the licence renewal procedure, and
triplet pregnancy rates could be reviewed during the clinics
annual inspection. Ultimately, the final decision as to which
policies are implemented will be influenced by a balance of the
cost of treatment cycles to the patient and the implications of
neonatal and long-term support for the children resulting from
multiple births. In a country such as the UK, where the support
costs fall to the National Health Service but the majority of
IVF is provided in the private sector, a legally supported policy
of multiple pregnancy limitation is essential and defendable.
Discussion
Although no consensus was reached about how to address the
problem of multiple pregnancies associated with OE or OI, it
was agreed that reducing multiple pregnancies constitutes a
major challenge for infertility treatment. However, OE in
particular presents a paradox, as the aim to enhance fertility
results in the complication of multiple pregnancies.
There is considerable difference both between countries and
clinics with regard to best clinical practice for the avoidance of
multiple pregnancies in women undergoing OI/OE procedures.
The increased risk of multiple pregnancies through ovulation
induction can be decreased, in principle, by switching patients
to IVF treatment, by reducing the number of follicles or by
cancelling the treatment cycle. Success in minimizing the
number of multiple pregnancies by using OI plus IUI within
strict criteria has been demonstrated by some physicians.
However, this raises the question of how national or
international controls or guidelines should be implemented or
changed, and by whom. It was proposed that a more
appropriate technique would be to use IUI without OE, which
often results in pregnancy in women who have been infertile
for many years. The results of the discussion suggest that the
pregnancy rate might be lower with this technique than when
IUI is combined with OE, thereby possibly avoiding the
increased risk of multiple pregnancies.
Embryo reduction has been used as a method of reducing
multiple pregnancies, but as this is considered an unsuitable
intervention in couples undergoing IVF, it is also an
inappropriate primary strategy for women undergoing OE.
Nevertheless, it may be acceptable as an emergency or salvage
procedure, as long as patients are well informed before
treatment about the associated risks and have agreed to
undergo this technique, if required or desired. It is recognized
that such programmes are not universally available or
universally permissible.
Although clinicians can do much to reduce the number of
multiple births through the use of appropriate techniques,
patient education is also important. Many patients focus solely
on the outcome of pregnancy, with an unrealistic view of what
may be achievable. Good patientdoctor communication is
important, and it was agreed that it is incumbent upon
clinicians to explain clearly any potential treatment and the
associated problems. Currently, media attention
sensationalizes the bizarre and unusual in infertility treatment,
whilst the problems of any resulting handicapped children in 537
 Infertility therapy-associated multiple births
high multiple pregnancy are not often addressed. Therefore,
professional or medical editing is important to ensure that
appropriate and balanced information is disseminated.
However, the way in which data are reported may also
influence their presentation in the media and subsequent
clinical practice. For example, defining clinical success rate as
the number of live singleton births, rather than by the
pregnancy rate, may affect patient perceptions of infertility
treatment. Reducing the focus on pregnancy rate may also
affect clinics decisions to transfer multiple embryos
unnecessarily.
Although it may be possible to reduce the incidence of
multiple births arising from OI/OE, currently there are no
recommendations for the techniques that should be used.
According to some physicians, the very nature of OI/OE is
such that it is not possible to modify the procedures so as to
eliminate the incidence of multiple gestation. In addition, an
acceptable incidence of multiple births has yet to be agreed
upon internationally. Appropriate patient, doctor and media
education is important if the multiple pregnancy rate is to be
reduced effectively.
Conclusions
Following on from the presentations and discussions, a statement
summarizing the conclusions and recommendations of the
participants was formulated, based on agreement upon a number
of settled debates (Box 1). In addition, a number of issues for
which a unanimous view has not yet been reached were
identified as requiring further research or discussion (Box 2).
Box 1. Settled debates.
Patients deserve and require all available information a
priori.
On-line prospective data reporting must include: (i)
cumulative singleton live birth rates per retrieval; (ii)
proportion of cancelled cycles; (iii) SET, DET and
blastocystsa; (iv) live twin and triplet birth rates; (v)
embryo reduction data where applicable; (vi) frozen
embryo transfer data if applicable.
With improved technology which has augmented the
pregnancy potential of pre-embryos with better selection
techniques and for other reasons, there comes the
recognized need to update current embryo transfer
guidelines in order to reduce the incidence of high-order
and twin gestation.
Embryo reduction, as such, is an unacceptable solution to
the multiple gestation challenge, but remains unavoidable
in certain high-risk cases.
An active and effective freezing programme is essential for
reducing or preventing altogether the occurrence of
infertility therapy-associated multiple gestation, as well as
other complications affecting patients health.
aThese statements not fully supported by L Veeck and Z Rosenwaks.
538
Finally, a number of directions for future activities to increase
awareness of the problems of multiple gestation associated
with infertility treatment, and to consider how best to address
this issue, were identified. These included:
(i) a role for participants in the meeting to serve as
ambassadors and educators in the ongoing efforts to reduce or
altogether prevent infertility therapy-associated multiple
gestation;
(ii) the intensification of educational efforts, directed at both
providers of infertility treatment and the public;
(iii) continued efforts to convene an Institute of Medicine
Committee on the challenge of infertility therapy-associated
multiple gestation;
(iv) convening a Bertarelli Foundation conference on optimal
and global data reporting;
(v) securing dependable data on the extent of multi-fetal
reduction;
(vi) undertaking regional studies under the auspices of the
Bertarelli Foundation, to establish the relative contributions of
IVF, OE and OI to infertility therapy-associated multiple
gestation;
(vii) convening a Bertarelli Foundation conference to develop
an optimal and, if at all possible, uniform global
embryo/blastocyst quality assessment system;
(viii) convening regional Bertarelli Foundation conferences
modelled on the present meeting to enhance national
awareness regarding infertility therapy-associated multiple
gestation;
(ix) convening a Bertarelli Foundation conference to define a
global consensus on what constitutes good or poor
prognosis IVF patients.
From this it is apparent that, despite the conclusions of the
present meeting, there is still much to be done if we are to
successfully overcome the problem of infertility therapy-
associated multiple gestation.
Box 2. Items for which unanimous agreement has not
been reached.
The role of the law versus guidelines only for the
prevention of IVF-associated multiple gestation.
The impact of insurance availability on the incidence of
infertility therapy-associated multiple gestation.
Data reporting: (i) singleton live birth per woman treated;
(ii) transitioning to per-patient versus per-annum
reporting.
Is twin pregnancy an acceptable outcome of ART?
Is there a need for age-dependent individualization of the
number of embryos transferred in the course of the IVF
procedure?
Has ovulation enhancement outlived its usefulness? Does it
still make sense?

Conference statement
The discipline of ART subscribes to the principle of
responsibility towards both the patients and their
children.
Infertility therapy-associated multiple gestation
constitutes a major physical, psychological and
financial challenge to couples and their children as
well as society as a whole.
The incidence of IVF-associated triplets is
plateauing or declining, whereas twin pregnancies
continue to increase.
Infertility therapy-associated multiple gestation
remains a challenge worldwide. The substantial
contribution of ovulation-induction and ovulation-
enhancement regimens remains a largely
unattended, major challenge.
Preventing, altogether, the occurrence of infertility
therapy-associated triplets must be viewed as an
initial goal. Reducing the incidence of twin
gestation is viewed as a follow-up goal.
Further progress towards reducing the incidence of
IVF-associated twin pregnancies would require
additional comparative prospective studies of the
impact, if any, of SET versus DET on the live-birth
rate. Improved means of assessing embryo quality
and uterine receptivity remains an ongoing
challenge.
The quality of an IVF programme is to be measured
by its ability to maximize the singleton birth rate,
rather than by its overall pregnancy rate.a
aThis statement not fully supported by L Veeck and Z Rosenwaks.
It should be noted that while the Centers for Disease Control
(CDC) provided information to inform debate, it played no
part in generating the final outcome or conclusions from the
meeting, and was not involved in endorsing the consensus
guidelines formulated.
References
Albano C, Platteau P, Nogueira D et al. 2001 Avoidance of multiple
pregnancies after ovulation induction by supernumerary
preovulatory follicular reduction. Fertility and Sterility 76,
820822.
Alin kerman B, Hovmller M, Rdestad A et al. 1995 Physical and
mental development in 46-year-old triplets. Acta Paediatrica 84,
661666.
AMBA 1984 Proposal submitted to the Federal Government
concerning Act of Grace payments for triplet and quadruplet
families. Australian Multiple Births Association.
American Society for Reproductive Medicine Practice Committee
1999 Guidelines on the Number of Embryos Transferred.
American Society for Reproductive Medicine, Birmingham, AL,
USA.
American Society for Reproductive Medicine, Society for Assisted
Reproductive Technology Registry 2002 Assisted reproductive
Infertility therapy-associated multiple births
technology in the United States: 1999 results generated from the
American Society for Reproductive Medicine/Society for
Assisted Reproductive Technology Registry. Fertility and Sterility
78, 918931.
Antman AM, Politch JA, Ginsburg ES 2002 Conversion of high-
response gonadotropin intrauterine insemination cycles to in vitro
fertilization results in excellent ongoing pregnancy rates. Fertility
and Sterility 77, 715720.
Balasch J, Fbregues F 2002 Is luteinizing hormone needed for
optimal ovulation induction? Current Opinion in Obstetrics and
Gynecology 14, 265274.
Balasch J, Miro F, Burzaco I et al. 1995 The role of luteinizing
hormone in human follicle development and oocyte fertility:
evidence from in-vitro fertilization in a woman with long-
standing hypogonadotrophic hypogonadism and using
recombinant human follicle stimulating hormone. Human
Reproduction 10, 16781683.
Behr B, Gebhardt J, Lyon J et al. 2002 Factors relating to a
successful cryopreserved blastocyst transfer program. Fertility
and Sterility 77, 697699.
Ben-Nun I, Cohen I, Shulman A et al. 1993 The inability of
preovulatory ovarian scan to predict multifetal pregnancy
occurrence in a follow-up of induction of ovulation with
menotropins. Fertility and Sterility 60, 781785.
Bergh C, Howles CM, Borg K et al. 1997 Recombinant human
follicle stimulating hormone (r-hFSH; Gonal-F) versus highly
purified urinary FSH (Metrodin HP): results of a randomized
comparative study in women undergoing assisted reproductive
techniques. Human Reproduction 12, 21332139.
Bergh C, Mller A, Nilsson L et al. 1999a Obstetric outcome and
psychological follow-up of pregnancies after embryo reduction.
Human Reproduction 14, 21702175.
Bergh T, Ericson A, Hillensjo T et al. 1999b Deliveries and children
born after in-vitro fertilisation in Sweden 198295: a
retrospective cohort study. Lancet 354, 15791585.
Botting BJ, Macfarlane AJ, Price FV (eds) 1990 Three, Four and
More: A Study of Triplets and Higher Order Births. HMSO,
London, UK. 246 pp.
Boulot P, Hedon B, Pelliccia G et al. 1993 Effects of selective
reduction in triplet gestation: a comparison of 80 cases managed
with or without this procedure. Fertility and Sterility 60,
497503.
Braat DD, Berkhout G, ten Brug CS et al. 1991 Multiple follicular
development in women with normal menstrual cycles treated with
pulsatile gonadotrophin-releasing hormone. Human Reproduction
6, 13791383.
Braat DD, Berkhout GM, ten Brug CS et al. 1992 Induction of
multiple follicular growth by pulsatile gonadotrophin-releasing
hormone (GnRH) treatment in women with normal cycles: the
role of the route of administration. Human Reproduction 7,
754757.
Bryan EM 1999a The death of a twin. In: Sandbank AC (ed.) Twin
and Triplet Psychology: A Professional Guide to Working with
Multiples, Routledge, London, UK. pp. 186200.
Bryan EM 1999b Twins with special needs In: Sandbank AC (ed.)
Twin and Triplet Psychology: A Professional Guide to Working
with Multiples. Routledge, London, UK. pp. 6169.
Callahan TL, Hall JE, Ettner SL et al. 1994 The economic impact of
multiple-gestation pregnancies and the contribution of assisted-
reproduction techniques to their incidence. New England Journal
of Medicine 331, 244249.
Centers for Disease Control and Prevention, American Society for
Reproductive Medicine, Society for Assisted Reproductive
Technology, RESOLVE 2002 2000 Assisted Reproductive
Technology Success Rates. Centers for Disease Control and
Prevention, Atlanta, GA, USA. 502 pp.
Centers for Disease Control and Prevention 2000 Contribution of
assisted reproductive technology and ovulation-inducing drugs to
triplet and higher-order multiple births United States
19801997. Morbidity and Mortality Weekly Report 49, 535538.
539
 Infertility therapy-associated multiple births
Chelmow D, Penzias A, Kaufman G et al. 1995 Costs of triplet
pregnancy. American Journal of Obstetrics and Gynecology 72,
677682.
Conde-Agudelo A, Belizan JM, Lindmark G 2000 Maternal
morbidity and mortality associated with multiple gestations.
Obstetrics and Gynecology 95, 899904.
Cook R, Bradley S, Golombok S 1998 A preliminary study of
parental stress and child behaviour in families with twins
conceived by in-vitro fertilization. Human Reproduction 13,
32443246.
Costello MF, Eden JA 2003 A systematic review of the reproductive
system effects of metformin in patients with polycystic ovary
syndrome. Fertility and Sterility 79, 113.
Couzinet B, Lestrat N, Brailly S et al. 1988 Stimulation of ovarian
follicular maturation with pure follicle stimulating hormone in
women with gonadotropin deficiency. Journal of Clinical
Endocrinology and Metabolism 66, 552556.
De Sutter P, Van der Elst J, Coetsier T et al. 2003 Single embryo
transfer and multiple pregnancy rate reduction in IVF/ICSI: a 5-
year appraisal. Reproductive Biomedicine Online 6, 464469.
Derom R, Derom C, Vlietinck R 2001 The risk of monozygotic
twinning. In: Blickstein I, Keith LG (eds) Iatrogenic Multiple
Pregnancy: Clinical Implications. Parthenon Publishing, New
York, NY, USA. pp. 919.
Dickey RP, Taylor SN, Lu PY et al. 2001 Relationship of follicle
numbers and estradiol levels to multiple implantation in 3,608
intrauterine insemination cycles. Fertility and Sterility 75, 6978.
Division of Reproductive Health, National Centre for Chronic
Disease Prevention and Health Promotion 2000 Contribution of
assisted reproductive technology and ovulation-inducing drugs to
triplet and higher-order multiple births United States
19801997. Morbidity and Mortality Weekly Report 49, 535538.
Dodson WC, Hughes CL Jr, Haney AF 1988 Multiple pregnancies
conceived with intrauterine insemination during superovulation:
an evaluation of clinical characteristics and monitored parameters
of conception cycles. American Journal of Obstetrics and
Gynecology 159, 382385.
Doyle P 1996 The outcome of multiple pregnancy. Human
Reproduction 11 (suppl. 4),110117.
Eddleman KA, Stone JL, Lynch L et al. 2000 Chorionic villus
sampling before multifetal pregnancy reduction. American
Journal of Obstetrics and Gynecology 183, 10781081.
ESHRE Campus Course Report 2001 Prevention of twin pregnancies
after IVF/ICSI by single embryo transfer. Human Reproduction
16, 790800.
Evans MI, Littmann L, St Louis L et al. 1995 Evolving patterns of
iatrogenic multifetal pregnancy generation: implications for
aggressiveness of infertility treatments. American Journal of
Obstetrics and Gynecology 172, 17501753.
Fanchin R, Ayoubi JM, Righini C et al. 2001 Uterine contractility
decreases at the time of blastocyst transfers. Human Reproduction
16, 11151119.
Farhi J, West C, Patel A et al. 1996 Treatment of anovulatory
infertility: the problem of multiple pregnancy. Human
Reproduction 11, 429434.
Fatemi HM, Platteau P, Albano C et al. 2002 Rescue IVF and
coasting with the use of a GnRH antagonist after ovulation
induction. Reproductive Biomedicine Online 5, 273275.
Fauser BC, Van Heusden AM 1997 Manipulation of human ovarian
function: physiological concepts and clinical consequences.
Endocrine Reviews 18, 71106.
Frydman R, Howles CM, Truong F 2000 A double-blind, randomized
study to compare recombinant human follicle stimulating
hormone (FSH; Gonal-F) with highly purified urinary FSH
(Metrodin HP) in women undergoing assisted reproductive
techniques including intracytoplasmic sperm injection. The
French Multicentre Trialists. Human Reproduction 15, 520525.
Gardner DK, Lane M 2003 Towards a single embryo transfer.
Reproductive Biomedicine Online 6, 470481.
Gardner DK, Surrey E, Minjarez D et al. 2003 Single blastocyst
540 transfer: a prospective randomized trial. Fertility and Sterility (in
press).
Gardner M, Goldenberg R, Cliver S et al. 1995 The origin and
outcome of preterm twin pregnancies. Obstetrics and Gynecology
85, 553557.
Garel M, Salobir C, Blondel B 1997a Psychological consequences of
having triplets: a 4-year follow-up study. Fertility and Sterility
67, 11621165.
Garel M, Stark C, Blondel B et al. 1997b Psychological reactions
after multifetal pregnancy reduction: a 2-year follow-up study.
Human Reproduction 12, 617622.
Germond M, Senn A 1999 A law affecting medically assisted
procreation is on the way in Switzerland. Journal of Assisted
Reproduction and Genetics 16, 341343.
Gerris J, De Neubourg D, Mangelschots K et al. 1999 Prevention of
twin pregnancy after in-vitro fertilization or intracytoplasmic
sperm injection based on strict embryo criteria: a prospective
randomized clinical trial. Human Reproduction 14, 25812587.
Gerris J, De Neubourg D, Mangelschots K et al. 2002 Elective single
day 3 embryo transfer halves the twinning rate without decrease
in the ongoing pregnancy rate of an IVF/ICSI programme.
Human Reproduction 17, 26262631.
Gianaroli L, Magli MC, Ferraretti AP et al. 1999 Preimplantation
diagnosis for aneuploidies in patients undergoing in vitro
fertilization with a poor prognosis: identification of the categories
for which it should be proposed. Fertility and Sterility 72,
837844.
Gleicher N, Oleske DM, Tur-Kaspa I et al., 2000 Reducing the risk
of high-order multiple pregnancy after ovarian stimulation with
gonadotropins. New England Journal of Medicine 343, 27.
Goldberg S, Perrotta M, Minde K et al. 1986 Maternal behavior and
attachment in low-birth-weight twins and singletons. Child
Development 57, 3446.
Goldenberg M, Rabinovici J, Shalev J et al. 1994 Lack of association
between ovarian follicular size and number and the occurrence of
multiple pregnancies in menotropin cycles. Gynecological
Endocrinology 8, 8387.
Goldfarb JM, Peskin B, Austin C et al. 1997 Evaluation of predictive
factors for multiple pregnancies during gonadotropin/IUI
treatment. Journal of Assisted Reproduction and Genetics 14,
8891.
Grifo J, Hoffman D, McNamee PI 2001 We are due for a
correction...and we are working to achieve one. Fertility and
Sterility 75, 14.
Guzick DS, Carson SA, Coutifaris C et al. 1999 Efficacy of
superovulation and intrauterine insemination in the treatment of
infertility. National Co-operative Reproductive Medicine
Network. New England Journal of Medicine 340, 177183.
Hay DA, Priot M, Collett S et al. 1987a Speech and language
development in preschool twins. Acta Geneticae Medicae et
Gemellologiae 36, 213223.
Hay DA, McIndoe R, OBrien PJ 1987b The older sibling of twins.
Australian Journal of Early Childhood 13, 2528.
Hedon B, Out HJ, Hugues JN et al. 1995 Efficacy and safety of
recombinant follicle stimulating hormone (Puregon) in infertile
women pituitary-suppressed with triptorelin undergoing in-vitro
fertilization: a prospective, randomized, assessor-blind,
multicentre trial. Human Reproduction 10, 31023106.
HFEA 2002 Patients Guide to IVF Clinics Provisional Data 2002.
http://www.hfea.gov.uk/Downloads/default.htm Human
Fertilisation and Embryology Authority.
Hillier SG, Smyth CD, Whitelaw PF et al. 1995 Gonadotrophin
control of follicular function. Hormone Research 43, 216223.
Homburg R, Howles CM 1999 Low-dose FSH therapy for
anovulatory infertility associated with polycystic ovary
syndrome: rationale, results, reflections and refinements. Human
Reproduction Update 5, 493499.
Human Fertilisation and Embryology Authority 2000 The Patients
Guide to IVF Clinics. HFEA, London, UK. 49 pp.
Jain T, Harlow BL, Hornstein MD 2002 Insurance coverage and
outcomes of in vitro fertilization. New England Journal of
Medicine 347, 661666.

Jones HW 2003 Multiple births: how are we doing? Fertility and
Sterility 79, 1721.
Kaufman G, Malone, F, Harvey-Wilkes K et al. 1998 Neonatal
morbidity and mortality associated with triplet pregnancy.
Obstetrics and Gynecology 91, 342348.
Kolibianakis EM, Devroey P 2002 The actual role of clomiphene
citrate. In: Reproduccion Humana, McGraw-Hill, Interamericana
De Epana S.A.U.
Kurachi K, Aono T, Suzuki M et al. 1985 Results of HMG
(Humegon)-HCG therapy in 6096 treatment cycles of 2166
Japanese women with anovulatory infertility. European Journal
of Obstetrics, Gynecology, and Reproductive Biology 19, 4351.
Lenton E, Soltan A, Hewitt J et al. 2000 Induction of ovulation in
women undergoing assisted reproductive techniques: recombinant
human FSH (follitropin alpha) versus highly purified urinary FSH
(urofollitropin-HP). Human Reproduction 15, 10211027.
Leyendecker G, Wildt L 1983 Induction of ovulation with chronic
intermittent (pulsatile) administration of Gn-RH in women with
hypothalamic amenorrhoea. Journal of Reproduction and Fertility
69, 397409.
Licciardi F, Berkeley AS, Krey L et al. 2001 A two- versus three-
embryo transfer: the oocyte donation model. Fertility and Sterility
75, 510513.
Lipitz S, Reichman BN, Uval J et al. 1994 A prospective comparison
of the outcome of triplet pregnancies managed expectantly or by
multifetal reduction to twins. American Journal of Obstetrics and
Gynecology 170, 874879.
Loumaye E, Engrand P, Shoham Z et al. 2003 Clinical evidence for
an LH ceiling effect induced by administration of recombinant
human LH during the late follicular phase of stimulated cycles in
World Health Organization type I and type II anovulation. Human
Reproduction 18, 314322.
Ludwig M, Schopper B, Katalinic A et al. 2000 Experience with the
elective transfer of two embryos under the conditions of the
german embryo protection law: results of a retrospective data
analysis of 2573 transfer cycles. Human Reproduction 15,
319324.
Luke B, Keith L 1992 The contribution of singletons, twins and
triplets to low birth weight, infant mortality and handicap in the
United States. The Journal of Reproductive Medicine 37,
661666.
Luke B, Bigger HR, Leurgans S et al. 1996 The cost of prematurity:
a case-control study of twins vs singletons. American Journal of
Public Health 86, 809814.
Lynch A, McDuffie R, Murphy J et al. 2001 Assisted reproductive
interventions and multiple birth. Obstetrics and Gynecology 97,
195200.
Magli MC, Gianaroli L, Ferraretti AP 2001 Chromosomal
abnormalities in embryos. Molecular and Cellular Endocrinology
183 (suppl. 1), S2934.
Marek D, Langley M, McKean C et al. 2000 Frozen embryo transfer
(FET) of day 5 blastocyst embryos compared to transfer of day 6
blastocyst embryos. Fertility and Sterility 74 (suppl. 1), S5253.
Martikainen H, Tiitinen A, Toms C et al. 2001 One versus two
embryo transfer after IVF and ICSI: a randomized study. Human
Reproduction 16, 19001903.
Martin JA, Hamilton BE, Ventura SJ et al. 2002 Births: Final Data
for 2001. National vital statistics reports Vol. 51, No. 2. National
Center for Health Statistics, Hyattsville, MD, USA. 104 pp.
Mnzo YJ, Nicollet B, Dumont M et al. 1993 Factors affecting
human blastocyst formation in vitro and freezing at the blastocyst
stage. Acta Europaea Fertilitatis 24, 207213.
Milki AA, Fisch JD, Behr B. 1999 Two-blastocyst transfer has
similar pregnancy rates and a decreased multiple gestation rate
compared with three-blastocyst transfer. Fertility and Sterility 72,
225228.
Munn S, Magli C, Cohen J et al. 1999 Positive outcome after
preimplantation diagnosis of aneuploidy in human embryos.
Human Reproduction 14, 21912199.
Navot D, Goldstein N, Mor-Josef S et al. 1991 Multiple pregnancies:
risk factors and prognostic variables during induction of
Infertility therapy-associated multiple births
ovulation with human menopausal gonadotrophins. Human
Reproduction 6, 11521155.
Nijs M, Geerts L, van Roosendaal E et al. 1993 Prevention of
multiple pregnancies in an in vitro fertilization program. Fertility
and Sterility 59, 12451250.
Norwitz ER 1998 Multiple pregnancy: trends, past, present, and
future. Infertility and Reproductive Clinics of North America 9,
351369.
Ostfeld BM, Smith RH, Hiatt M et al. 2000 Maternal behavior
toward premature twins: implications for development. Twin
Research 3, 234241.
Out HJ, Mannaerts BM, Driessen SG et al. 1995 A prospective,
randomized, assessor-blind, multicentre study comparing
recombinant and urinary follicle stimulating hormone (Puregon
versus Metrodin) in in-vitro fertilization. Human Reproduction
10, 25342540.
Ozturk O, Templeton A 2002 In-vitro fertilisation and risk of
multiple pregnancy. Lancet 359, 232.
Ozturk O, Bhattacharya S, Templeton A 2001 Avoiding multiple
pregnancies in ART: evaluation and implementation of new
strategies. Human Reproduction 16, 13191321.
Papiernik E 1983 Social cost of twin births. Acta Geneticae Medicae
et Gemellologiae 32, 105111.
Papiernik E 1991 Costs of multiple pregnancies. In: Harvey D, Bryan
EM (eds) The Stress of Multiple Births. Multiple Births
Foundation, London, UK. pp. 2234.
Pasqualotto EB, Falcone T, Goldberg JM et al. 1999 Risk factors for
multiple gestation in women undergoing intrauterine insemination
with ovarian stimulation. Fertility and Sterility 72, 613618.
Paulson RJ, Ory SJ, Giudice LC et al. 2001 Multiple pregnancies:
what action should we take? Fertility and Sterility 75, 1415.
Pelinck MJ, Hoek A, Simons AH et al. 2002 Efficacy of natural
cycle IVF: a review of the literature. Human Reproduction
Update 8, 129139.
Petterson B, Nelson K, Watson L et al. 1993 Twins, triplets, and
cerebral palsy in births in Western Australia in the 1980s. British
Medical Journal 307, 12391243.
Pharoah PO, Cooke T 1996 Cerebral palsy and multiple births.
Archives of Disease in Childhood. Fetal and Neonatal Edition 75,
F174177.
Recombinant Human FSH Study Group 1995 Clinical assessment of
recombinant human follicle-stimulating hormone in stimulating
ovarian follicular development before in vitro fertilization.
Fertility and Sterility 63, 7786.
Reynolds MA, Schieve LA, Martin JA et al. 2003a Trends in
multiple births conceived using assisted reproductive technology,
United States, 19972000. Pediatrics 111, 11591162.
Reynolds MA, Schieve LA, Jeng, G et al. 2003b Does insurance
coverage decrease the risk for multiple births associated with
assisted reproductive technology? Fertility and Sterility 80,
1623.
Rochon M, Stone J 2003 Invasive procedures in multiple gestations.
Current Opinion in Obstetrics and Gynecology 15, 165175.
Ruiz RJ, Brown CE, Peters MT et al. 2001 Specialized care for twin
gestations: improving newborn outcomes and reducing costs.
Journal of Obstetric, Gynecologic, and Neonatal Nursing 30,
5260.
Russell RB, Petrini, JR, Damus K et al. 2003 The changing
epidemiology of multiple births in the United States. Obstetrics
and Gynecology 101, 129135.
Rydhstrem H, Heraib F 2001 Gestational duration, and fetal and
infant mortality for twins vs. singletons. Twin Research 4,
227231.
Schats R, Sutter PD, Bassil S et al. 2000 Ovarian stimulation during
assisted reproduction treatment: a comparison of recombinant and
highly purified urinary human FSH. On behalf of The Feronia
and Apis Study Group. Human Reproduction 15, 16911697.
Scher A, Petterson B, Blair E et al. 2002 The risk of mortality or
cerebral palsy in twins: a collaborative population-based study.
Pediatric Research 52, 671681.
Schieve LA, Peterson HB, Meikle SF et al. 1999 Live-birth rates and 541
 Infertility therapy-associated multiple births
multiple-birth risk using in vitro fertilization. The Journal of the
American Medical Association 282, 18321838.
Schreiner-Engel P, Walther VN, Mindes J et al. 1995 First-trimester
multifetal pregnancy reduction: acute and persistent psychologic
reactions. American Journal of Obstetrics and Gynecology 172,
541547.
Sebire N, Snijders R, Hughes K et al. 1997 The hidden mortality of
monochorionic twin pregnancies. British Journal of Obstetrics
and Gynaecology 104, 12031207.
Sebire N, Jolly M, Harris J et al. 2001 Risks of obstetric
complications in multiple pregnancies. An analysis of more than
400 000 pregnancies in the UK. Prenatal and Neonatal Medicine
6, 8994.
Senat M, Ancel P, Bouvier-Colle M et al. 1998 How does multiple
pregnancy affect maternal mortality and morbidity? Clinical
Obstetrics and Gynecology 41, 7883.
Shapiro BS, Richter KS, Harris DC et al. 2001 A comparison of day
5 and day 6 blastocyst transfers. Fertility and Sterility 75,
11261130.
Shelden R, Kemmann E, Bohrer M et al. 1988 Multiple gestation is
associated with the use of high sperm numbers in the intrauterine
insemination specimen in women undergoing gonadotropin
stimulation. Fertility and Sterility 49, 607610.
Shoham Z 2002 The clinical therapeutic window for luteinizing
hormone in controlled ovarian stimulation. Fertility and Sterility
77, 11701177.
Shoukir Y, Campana A, Farley T et al. 1997 Early cleavage of in-
vitro fertilized human embryos to the 2-cell stage: a novel
indicator of embryo quality and viability. Human Reproduction
12, 15311536.
Soules MR, Chang RJ, Lipshultz LI et al. 2001 Multiple
pregnancies: action is taking place. Fertility and Sterility 75,
1516.
Staessen C, Janssenswillen C, Van den Abbeel E et al. 1993
Avoidance of triplet pregnancies by elective transfer of two good
quality embryos. Human Reproduction 8, 16501653.
Staessen C, Nagy ZP, Liu J et al. 1995 One years experience with
elective transfer of two good quality embryos in the human in-
vitro fertilization and intracytoplasmic sperm injection
programmes. Human Reproduction 10, 33053312.
Stone J, Eddleman K, Lynch L et al. 2002 A single center experience
with 1000 consecutive cases of multifetal pregnancy reduction.
American Journal of Obstetrics and Gynecology 187, 11631167.
Tan SL, Child TJ 2002 In-vitro maturation of oocytes from
unstimulated polycystic ovaries. Reproductive Biomedicine
Online 4 (suppl. 1), 1823.
Tasdemir M, Tasdemir I, Kodama H et al. 1995 Two instead of three
embryo transfer in in-vitro fertilization. Human Reproduction 10,
21552158.
Templeton A 2000 Avoiding multiple pregnancies in ART: replace as
many embryos as you like one at a time. Human Reproduction
15, 1662.
Templeton A, Morris JK 1998 Reducing the risk of multiple births by
transfer of two embryos after in vitro fertilization. New England
Journal of Medicine 339, 573577.
Templeton A, Morris JK, Parslow W 1996 Factors that affect
outcome of in-vitro fertilisation treatment. Lancet 348,
14021406.
Tesarik J, Greco E 1999 The probability of abnormal preimplantation
development can be predicted by a single static observation on
pronuclear stage morphology. Human Reproduction 14,
13181323.
Testart J, Lassalle B, Belaisch-Allart J et al. 1986 High pregnancy
rate after early human embryo freezing. Fertility and Sterility 46,
268272.
The ESHRE Capri Workshop Group 2000 Multiple gestation
pregnancy. Human Reproduction 15, 18561864.
The European IVF-monitoring programme (EIM), for the European
Society of Human Reproduction and Embryology (ESHRE) 2002
Assisted reproductive technology in Europe, 1999. Results
542
generated from European registers by ESHRE. Human
Reproduction 17, 32603274.
The European Recombinant Human LH Study Group 1998
Recombinant human luteinizing hormone (LH) to support
recombinant human follicle-stimulating hormone (FSH)-induced
follicular development in LH- and FSH-deficient anovulatory
women: a dose-finding study. Journal of Clinical Endocrinology
and Metabolism 83, 15071514.
The European Recombinant Human LH Study Group 2001 Human
recombinant luteinizing hormone is as effective as, but safer than,
urinary human chorionic gonadotropin in inducing final follicular
maturation and ovulation in in vitro fertilization procedures:
results of a multicenter double-blind study. Journal of Clinical
Endocrinology and Metabolism 86, 26072618.
Thorpe K, Golding J, MacGillivray I et al. 1991 Comparison of
prevalence of depression in mothers of twins and mothers of
singletons. British Medical Journal 302, 875878.
Tiitinen A, Halttunen M, Hrkki P et al. 2001 Elective single embryo
transfer: the value of cryopreservation. Human Reproduction 16,
11401144.
Tough SC, Greene CA, Svenson LW et al. 2000 Effects of in vitro
fertilization on low birth weight, preterm delivery, and multiple
birth. The Journal of Pediatrics 136, 618622.
Tur R, Barri PN, Coroleu B et al. 2001 Risk factors for high-order
multiple implantation after ovarian stimulation with
gonadotrophins: evidence from a large series of 1878 consecutive
pregnancies in a single centre. Human Reproduction 16,
21242129.
Valbuena D, Simon C, Romero JL et al. 1996 Factors responsible for
multiple pregnancies after ovarian stimulation and intrauterine
insemination with gonadotropins. Journal of Assisted
Reproduction and Genetics 13, 663668.
Van Royen E, Mangelschots K, De Neubourg D et al. 2001
Calculating the implantation potential of day 3 embryos in
women younger than 38 years of age: a new model. Human
Reproduction 16, 326332.
Vilska S, Tiitinen A, Hydn-Granskog C et al. 1999 Elective transfer
of one embryo results in an acceptable pregnancy rate and
eliminates the risk of multiple birth. Human Reproduction 14,
23922395.
Warnock M 1985 A Question of Life: The Warnock Report on Human
Fertilisation and Embryology. Basil Blackwell, Oxford, UK. 110
pp.
Waterstone J, Parsons J, Bolton V 1991 Elective transfer of two
embryos. Lancet 337, 975976.
White DM, Polson DW, Kiddy D et al. 1996 Induction of ovulation
with low-dose gonadotropins in polycystic ovary syndrome: an
analysis of 109 pregnancies in 225 women. Journal of Clinical
Endocrinology and Metabolism 81, 38213824.
Woodward J 1998 The Lone Twin. Understanding Twin Bereavement
and Loss. Free Association Books, London, UK.
Yokoyama Y, Shimizu T, Hayakawa K. 1995 Incidence of handicaps
in multiple births and associated factors. Acta Geneticae Medicae
et Gemellologiae 44, 8191.
Yu SL, Pepperell RJ, Evans JH 1991 Can ultrasonography reliably
predict the occurrence of multiple pregnancies in gonadotrophin
ovulation induction? The Australian and New Zealand Journal of
Obstetrics and Gynaecology 31, 5862.