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Article
Clinical and biological parameters influencing
implantation: score to determine number of
embryos to transfer
Dr Florence Lesourd obtained her MD degree and her speciality degree in Obstetrics and
Gynaecology in 1993 in the University of Toulouse, France. She has been in charge of the
IVF clinic of the Paule de Viguier University Hospital in Toulouse since 1997. Her current
research interests include reproductive endocrinology and clinical factors influencing the
outcome of assisted reproduction treatments.

Dr Florence Lesourd
Florence Lesourd, Olivier Parant, Muriel Clouet-Delannoy, Jean Parinaud1
Pôle d’Obstétrique, Gynécologie et Médecine de la Reproduction, Hôpital Paule de Viguier, 330 avenue de Grande
Bretagne, TSA 70034, 31059 Toulouse Cedex 9, France
1
Correspondence: Tel: +33 5 67771007; Fax: +33 5 67771006; e-mail: parinaud.j@chu-toulouse.fr

Abstract
Choosing the number of embryos to be transferred is a major problem in assisted reproductive technologies. This study
aimed to establish and validate a score predicting implantation rates in order to help in the choice of the number of embryos
to be transferred, allowing the best compromise between high pregnancy rate and low multiple pregnancy risk. Clinical
and biological parameters influencing implantation rates were retrospectively analysed in 739 embryo transfers and an
implantation score was established. This score was then prospectively validated in 521 embryo transfers. Three parameters
(age, ovarian response to FSH stimulation and embryo morphology) appeared to be predictive of the implantation rates and
were included in an implantation score (3–9). The prospective study confirmed the validity of the score since implantation
rates were higher when the score increased (5.9% for score 3 versus 22.4% for score 9; P < 0.05). Therefore, success rates can
be predicted by the implantation score, which is of clinical value in choosing the number of embryos to be transferred in order
to decrease multiple pregnancies while keeping high pregnancy rates. However, choosing the right number of embryos to be
transferred needs further studies, since the percentage of multiple pregnancies remained relatively high in this prospective
study (27%)

Keywords: age, embryo morphology, embryo transfer, implantation rate, multiple pregnancies, ovarian stimulation

Introduction
The efficiency of assisted reproductive technologies, and
especially IVF and intracytoplasmic sperm injection (ICSI),
has dramatically increased in recent years. This progress had
the unfortunate side effect of increasing multiple pregnancies.
Therefore, limiting the risk of multiple pregnancies has become
one of major goals in assisted reproduction (Gerris et al.,
2000; Hernandez, 2001; Ozturk et al., 2001). Indeed, multiple
pregnancies are associated with severe complications and high
morbidity due to prematurity and low birth weight (ESHRE
Capri Workshop Group, 2000). Nevertheless, several studies
have shown that the variables affecting multiple pregnancy rate
also influence the total pregnancy rate (Engmann et al., 2001;
Zegers-Hochschild et al., 2004; Elizur et al., 2005).
The best way to avoid multiple pregnancy is to transfer only
one or two embryos (Gerris et al., 1999; Vilska et al., 1999;
Elizur et al., 2005). However, such a policy does not take into
account factors affecting success rates and has to be modulated
according to patients’ characteristics (Hernandez, 2001);
moreover, it necessitates a good cryopreservation programme
in order to provide a good cost-effective practice (Tiitinen et
al., 2001).
Numerous studies have reported factors influencing implantation
rates. The main factors were patient’s age (Roseboom et al.,
1995; Devroey et al., 1996; Strandell et al., 2000; Engmann et
al., 2001; Elizur et al., 2005), ovarian response to stimulation
(Chang et al., 1998) and embryo morphology (Gerris et al., 453
 Article - Determination of number of embryos to be transferred - F Lesourd et al.
1999; Bos-Mikich et al., 2001; Lundin et al., 2001; Terriou et
al., 2001; Van Royen et al., 2001). The ovarian reserve and the
oocyte quality decrease with increasing age. The incidence of
oocyte chromosome degeneration, meiotic non-disjunction and
aneuploidy in embryos increases with age (Munné et al., 1995;
Volarcik et al., 1998) and concomitantly the implantation rate
during IVF, decreases (van Kooij et al., 1996). Therefore, the
woman’s age is a good predictor of pregnancy rate, but it is not
the only one. The gonadotrophin requirement is also a direct
indicator of ovarian reserve and appears to identify qualitative
differences in the oocytes produced (Kailasam et al., 2004).
Poor responders require markedly increased quantities of
gonadotrophins to produce follicles, and they have low peak
oestradiol concentrations, low numbers of mature oocytes and
lower fertilization, implantation and pregnancy rates (Surrey
et al., 2000; Weissman et al., 2003). The inverse relationship
between total gonadotrophin dose used during stimulation and
IVF success is well established (Stadtmauer et al., 1994). To
define the ovarian response to FSH, it is preferable to use the
ratio of oestradiol concentration on the day of human chorionic
gonadotrophin (HCG) to the total number of injected FSH
units rather than by the number of oocytes recovered or the
serum peak oestradiol concentration (Hugues et al., 1991),
since this parameter avoids discrepancies in protocols. Age
and gonadotrophin requirement are often linked, but they
are independent indicators of ovarian reserve. Recently, the
pharmacogenetic approach of including genetic factors (Greb
et al., 2005) and the pharmacological approach including the
physicochemical characterization of FSH (Keck et al., 2005)
improved the understanding of the ovarian sensitivity to
exogenous FSH.
The aim of the present study was to establish an objective
prognostic score for the prediction of implantation rates
according to clinical and biological parameters and to validate
this score in a prospective study.
Materials and methods
Retrospective study
Patients
A total of 739 transfers performed from September 1999 to
December 2000 in 515 patients (aged 33.9 ± 3.9 years) were
analysed. The causes of infertility were as follows: male
factor (54.7%), tubal damage (26.7%), unexplained fertility
(8.1%), ovarian dysfunction (5.1%), endometriosis (2.9%)
and cervical pathology (2.5%). This distribution reflected the
usual distribution in this centre.
Ovarian stimulation
Ovarian stimulation was performed using a combination
of triptorelin (Decapeptyl, Ipsen, Paris, France) and
recombinant FSH (Gonal-F; Serono, Paris, France) (mean
total FSH injected: 2451 ± 1173 IU) as previously described
(Parinaud et al., 1993), the daily dose varying from 75 to 300
IU according to clinical criteria (hormone concentrations, age
and body mass index). Two to 23 oocytes (mean: 9.1) were
collected by ultrasonically guided puncture.
454
IVF procedures (n = 320)
After liquefaction for 30 min at 37°C, motile spermatozoa
were isolated using a discontinuous (95, 80, 60%) Pure
Sperm gradient (Nidacon, Göteborg, Sweden). Following
centrifugation for 20 min at 300 g, the 90% fraction was
recovered and sperm cells were then washed once with
SpermFit medium (Ellios Bio-Media, Paris, France). The final
pellet was resuspended in fertilization medium (Cook, Paris,
France). The oocytes were placed in fertilization medium
(Cook). They were inseminated with 50,000 spermatozoa in
cases of normal spermatozoa and with 200,000 spermatozoa
in cases of abnormal spermatozoa according to WHO criteria
(World Health Organization, 1992). After a 24-h incubation,
the oocytes were observed for pronuclei assessment, and
then transferred in cleavage medium (Cook). Embryos
were observed for quality scoring according to Giorgetti
et al. (1995) 48 h after follicular puncture (at the 2-cell or
4-cell stage). This score varied from 1 to 4 points as follows:
a cleaved embryo received 1 point, and an additional point
was added for each of the following features: achieving the
4-cell stage, an absence of irregular cells and an absence of
anucleate fragments (or ≤20% of embryonic surface).
ICSI procedures (n = 419)
After liquefaction for 30 min at 37°C, motile spermatozoa
were isolated using a discontinuous (95, 80, 60%) Pure
Sperm gradient (Nidacon, Göteborg, Sweden). Following
centrifugation for 20 min at 300 g, the 90% fraction was
recovered and sperm cells were then washed once with
SpermFit medium (Ellios Bio-Media, Paris, France). The final
pellet was resuspended in fertilization medium containing 5%
polyvinylpyrrolidone solution (PVP, Medicult, Denmark).
ICSI procedures were as previously described (Calderon et
al., 1995); briefly oocytes were denuded of cumulus cells
with hyaluronidase (Hyase, Scandinavian IVF Science,
Gothenburg, Sweden) and corona cells were removed
mechanically. Sperm were injected using micro-injection
pipettes (Cook, Paris, France) after breaking the tail with
the tip of the pipette. After injection the oocytes were placed
in 0.8 ml of cleavage medium on a 4-well dish (Nunc,
Denmark). Between 16 and 20 h after the ICSI procedure,
oocytes were observed for the presence of pronuclei. After
48 h, the embryos were observed and classified, using the
same criteria as for IVF, according to the score established by
Giorgetti et al. (1995).
Embryo transfers
Transfers were performed 48 h after oocyte collection under
ultrasound-guidance. Two to four embryos were transferred
(2.6 ± 0.9) resulting in 210 (28%) clinical pregnancies,
defined by the presence of a fetal heart activity, with a
13.9% implantation rate (number of fetal hearts/number of
transferred embryos). Out of the pregnancies, 52 (25%) were
twin and nine (4%) were triplet. Twenty-four pregnancies
(11%) resulted in miscarriages, one induced abortion for
congenital abnormality (0.5%), six (3%) were ectopic and
179 (85%) delivered.
 Article - Determination of number of embryos to be transferred - F Lesourd et al.
Prospective study
In all, 521 transfers performed from January 2001 to
December 2002 in 392 patients (aged 33.0 ± 4.2 years) were
analysed. The causes of infertility were as follows: male
factor (56.1%), tubal damage (25.4%), unexplained fertility
(6.9%), ovarian dysfunction (3.7%), endometriosis (4.3%)
and cervical pathology (3.5%).
The IVF (n = 216) and ICSI (n = 305) procedures were
identical to the retrospective study.
The number of transferred embryos was chosen according to
the score established in the retrospective study: four embryos
if the score was lower than 6 (n = 93), three embryos if the
score was equal to 6 (n = 164) and two embryos when the
score was higher than 6 (n = 264). Only patients having at
least as many embryos as the number given by the score
were included in the study. The mean number of transferred
embryos was 2.7 ± 0.8.
Statistical analysis
Data are means ± SD. Student’s t-test and Chi-squared test
were used as appropriate. Correlations were assessed through
Pearson coefficient.
Results
Factors influencing the implantation
rates
To study the predictive value of parameters, the implantation
rates have been compared according to groups defined as lower
to the 25th percentile, between the 25th and the 75th percentile
and higher than the 75th percentile. The studied parameters were
the ones reported in previous studies as influencing pregnancy
rates. This study has also investigated the ovarian response
to stimulation defined as the ratio of oestradiol concentration
on the day of HCG to the number of injected FSH units
(oestradiol/n FSH units) (Hugues et al., 1991). Table 1 reports
the threshold values (25th and 75th percentile) for each studied
parameter. Table 2 shows that the most predictive factors on
implantation rates are age and oestradiol/n FSH units, which
are poorly linked together (r2 = 0.031).
The influence of the attempt rank was also studied, and no
significant difference in implantation rates was found (15.1%
for the first; 14.1 for the second, 11.9 for the third, 11.7 for
the fourth and 13.2 for the fifth).
Since several embryos with different scores were transferred,
the transfers have been graded in the following manner:
grade 4 when at least one score 4 embryo was transferred,
grade 3 when no score 4 but at least one score 3 embryo
was transferred, grade 2 when neither score 4 nor score 3
but at least one score 2 embryo was transferred and
grade 1 when only score 1 embryos were transferred.
The implantation rates were highly statistically different
between the grades (19.5% for grade 4, 13.2% for grade 3,
9.1% for grade 2 and 2.7% for grade 1; P < 0.001).
Establishment of a score for predicting
implantation rates
Taking into account these data, a score was established
for the most predictive parameters (age, oestradiol/n
FSH units, embryo score) as reported in Table 3. The
implantation score was equal to the sum of the 3 scores.
Figure 1 reports the implantation rates according to the
implantation score and shows a significant increase in
implantation rate according to the implantation score
(P < 0.01).
Prospective evaluation of the score
The implantation score, established in the retrospective
study, was applied prospectively to 521 transfers. The
number of transferred embryos was chosen as follows:
four embryos when the implantation score was <6 (n = 93),
three embryos when it was equal to 6 (n = 164) and two
embryos when it was >6 (n = 264). A total of 172 (33%)
clinical pregnancies were obtained with a 15% implantation
rate. Out of the pregnancies, 41 (24%) were twin and
six were (3%) triplet. The outcome of pregnancies was as
follows: 36 miscarriages (21%), two ectopic pregnancies
(1%), three induced abortions for congenital abnormalities
(2%) and 131 deliveries (76%) (100 singletons and 31
twins). It must be noted that from the eight triplet
pregnancies, seven spontaneously reduced (one singleton
and six twins), while one was medically reduced to a
twin pregnancy. Figure 1 reports the implantation
rate according to the score. It appears that implantation
rate significantly increased with the score (P < 0.01). In order
to compensate for differences in implantation rates, the
number of transferred embryos varied as a function of
the implantation score (see materials and methods above).
This resulted in no significant differences in pregnancy
rates between the scores (29, 41, 28, 31, 39, 29, 31%
respectively for score 3, 4, 5, 6, 7, 8 and 9). However, as
shown in Figure 2, there was an increase in the incidence
of multiple pregnancies when transferring four embryos (23,
32 and 50% respectively for two, three and four embryos; P
< 0.05).
When studying 131 transfers where only one embryo was
available, the implantation rate according to the transfer
score was as follows: 0% for scores 3 and 4, 4% for score
5, 11% for score 6, 19% for score 7 and 30% for score 8 (P
= 0.067).
Embryo freezing was performed in 142 cycles (25%). The
mean number of frozen embryos was 2.8 ± 1.9. There were
101 cases of embryo thawing leading to 20 pregnancies
(20%) (four miscarriages, one ectopic, 12 deliveries and
three ongoing).
Discussion
Multiple pregnancies are a major problem associated with
assisted reproduction. They are associated with increased risks
to the health of both mother (Conde-Agudelo et al., 2000) and
children (Russell et al., 2003) when compared with singleton 455
 Article - Determination of number of embryos to be transferred - F Lesourd et al.

Table 1. Values of the 25th and 75th percentile of the main studied
parameters (n = 739).

25th 75th
percentile percentile

Age (years) 31 36
Basal FSH (IU/l) 5.1 7.6
Oestradiol on day of HCG (pg/ml) 1150 2053
Total FSH injected (IU) 1700 2850
Number of follicles ≥15 mm 5 9
Oestradiol/n FSH units 0.437 1.066
Number of collected oocytes 5 11
Number of obtained embryos 2 6
Fertilization rate (%) 40 75

Table 2. Implantation rates according to the groups of the different parameters. NS = not
statistically significant. Data are mean values.

Group 1 Group 2 Group 3 Statistical

(n = 184) (n = 370) (n = 185) comparisons

Age (years) 15.9 16.3 8.9 P < 0.01 (1–3 and 2–3)
Basal FSH 13.1 16.5 10.3 P < 0.05 (2–3)
Oestradiol on day of HCG 12.3 14.1 16.0 NS
Number of injected FSH units 17.8 14.1 10.8 P < 0.05 (1–3)
Number of follicles ≥15 mm 11.4 14.6 15.3 NS
Oestradiol/n FSH units 10.1 14.3 17.5 P < 0.01 (1–3)
Number of collected oocytes 10.1 15.6 13.6 NS
Number of obtained embryos 16.0 13.5 13.8 NS
Fertilization rate 13.1 14.6 14.6 NS

Group 1: <25th percentile; group 2: 25th–75th percentile; group 3: >75th percentile.

Table 3. Threshold values of each parameter and their subsequent scores.

Score 1 2 3

Age (years) >36 31–36 <31

Oestradiol/n FSH units <0.437 0.437–1.066 >1.066
Embryo quality Only score 2 or No score 4 but at least At least one
score 1 embryos one score 3 embryo score 4 embryo

456
 Article - Determination of number of embryos to be transferred - F Lesourd et al.

Figure 1. Implantation rates according to the implantation Figure 2. Multiple gestation rate according to the number of
score in the retrospective and prospective studies. P < 0.01 in transferred embryos. P < 0.05 for four transferred embryos
both studies. versus 2 and 3.

Figure 3. Proposed flow chart for the choice of the number of embryos to be transferred according to the score.

457
 Article - Determination of number of embryos to be transferred - F Lesourd et al.
pregnancies. For mothers the risks include hypertensive
disorders, thrombo-embolisms, anaemia and vaginal–uterine
haemorrhages. The rate of Caesarean section increases with
the number of fetuses. Mortality rates of 14.9 per 100,000
pregnancies have been reported in Europe in 1994 for multiple
pregnancies compared with 5.2 for singleton pregnancies in
the same period (Senat et al., 1998). For babies, many of the
perinatal complications are attributable to pre-term delivery and
low birth weight. The risks include high-grade intraventricular
haemorrhage, necrotizing enterocolitis and respiratory distress
syndrome (Gardner et al., 1995). The risk of handicap increases
with the number of fetuses (Petterson et al., 1993). These
health problems can lead to psychological and social concerns
and have significant economic implications both for the family
involved and for the healthcare system (Koivurova et al., 2004).
Some countries have adopted measures, through legislation or
development of clinical guidelines, to decrease their frequency
(Antoine et al., 2004). In France, there is no national consensus.
Assisted reproduction centres are beginning to test measures to
reduce the multiple pregnancy rates maintaining an acceptable
total pregnancy rate. In the authors’ centre a score is adopted.
Indeed, since multiple parameters have an influence on
implantation rates, prediction is necessarily multivariate. The
aim of the study was to include different parameters in a score.
Since a score is always established through a retrospective
study, it must be validated in a prospective one (Stolwijk et al.,
1998). The results of this prospective study have confirmed the
validity of the score, which allows the identification of groups
with different prognosis.
Out of the studied parameters the age and the quality of
embryos appeared to be discriminant for success rates, as
largely reported in previous studies (Roseboom et al., 1995;
Devroey et al., 1996; Gerris et al., 1999; Strandell et al., 2000;
Bos-Mikich et al., 2001; Engmann et al., 2001; Lundin et
al., 2001; Terriou et al., 2001; Van Royen et al., 2001). The
third predictive parameter was the ovarian response to FSH
stimulation as assessed by the ratio of oestradiol concentration
on the day of HCG to the total number of injected FSH units.
This way of evaluating ovarian response is rather unusual, but
it may be understood to represent ovarian sensitivity (Hugues et
al., 1991). This is in good agreement with the study of Strandell
et al. (2000) that reported a negative correlation between birth
and total FSH doses. Similarly, Chang et al. (1998) found that
both gonadotrophin dosage and oestradiol concentration on the
day of HCG were significantly related to the number of antral
follicles detected at the beginning of the treatment cycle, which
was highly predictive of success rates. In the present study,
oestradiol/n FSH units appeared to have a better discriminant
value for implantation rate than total FSH dosage and oestradiol
concentrations by themselves.
In agreement with another study (Terriou et al., 2001), the rank
of the attempt did not have any influence on the outcome of
the attempt, but it must be pointed out that no more than five
attempts were performed, and it is not possible to speculate on
a decrease after the fifth attempt. Moreover, patients with low
chances of pregnancies due to low results in previous cycles did
not continue attempts so that there is a selection of patients with
a good prognosis for high ranked attempts.
Although there was a trend for an increase in implantation
458 rate in patients with high numbers of oocytes, it did not reach
significance. This finding fits well with previous studies, since
Strandell et al. (2000) have found no influence of oocyte number
on pregnancy rate, while Terriou et al. (2001) have reported it
as a predictive parameter. Therefore, it can be concluded that if
this parameter has an influence, this influence is weak.
In conclusion, the establishment of an implantation score is
of clinical interest in order to adapt the number of embryos to
be transferred according to clinical and biological parameters.
A systematic policy of transferring one or two embryos is
difficult to use since chances of pregnancy and thus risk of
multiple pregnancy have huge variations from one patient to
another. However, since embryo quality appears to be one
of the most effective parameters, efforts have to be made to
achieve a better appreciation of the development ability of the
embryos and metabolic measurements could be a potential way
(Gardner et al., 2001). However, in the prospective study, the
multiple pregnancy rate remained high, suggesting that too
many embryos were transferred. Therefore it would be better to
transfer one embryo for score ≥7, two for score equal to 6 and
three for score <6 (Figure 3).
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