Human Reproduction vol.13 no.2 pp.403-408, 1998
Predictive value of the results of a first in-vitro
fertilization cycle on the outcome of subsequent cycles
Carolyn A.Croucherl, Amir Lass, Raul Margara
and Robert M.Winston
Institute of Obstetrics & Gynaecology, Royal Postgraduate Medical
School, Hammersmith Hospital, London W12 OHS, UK
1To whom correspondence should be addressed at: Department of
Obstetrics and Gynaecology, St Helier Hospital, Carshalton, Surrey
SM5 1AA, UK
This study examines the relationship between the first cycle
of in-vitro fertilization (IVF) and subsequent cycles. The
results of all IVF cycles conducted at The Hammersmith
Hospital or The Royal Masonic Hospital between 1988 and
1995 were studied including those cycles where egg recovery
was abandoned due to poor ovarian response. All patients
underwent a standardized treatment protocol. Of those
women who achieved a clinical pregnancy during their
first IVF attempt, 33% achieved a pregnancy during their
second cycle, statistically significantly different from the
24% of patients conceiving during a second cycle who had
failed to conceive during their first. 36% of those who
achieved a biochemical pregnancy in their first cycle became
pregnant in their second. Age was an important factor in
the success of IVF treatment, with pregnancy rates of 48%
in the 20-25 year age group falling to 8% in those aged
~41 years. Cumulative pregnancy rates were 26% after
one cycle, increasing to 43% after two cycles and reached
80% after seven cycles. A previous pregnancy significantly
improved a couple's probability of conception in a later
IVF cycle. Overall pregnancy rates per cycle were constant
for the first three attempts. Cumulative pregnancy rates
continued to rise to 72% after six cycles. Thus the more
cycles a couple undergo (up to six) the greater their chance
of a pregnancy.
Key words: cumulative pregnancy rates/cycle number/IVF
Introduction
Couples undergoing in-vitro fertilization (IVF) are faced with
considerable uncertainty. Because the chance of conception
with a single treatment is still low, treatment cycles cannot be
realistically considered in isolation. Calculation of cumulative
pregnancy rates are needed as are trends in success rates with
repeated cycles. Those women returning for a repeated IVF
attempt, having delivered a live infant after a previous IVF
cycle, are reported to have a better prognosis (Molloy et al.,
1995). The aim of this study was to assess those cycles which
had been successful, where a large database of patients had
been accumulated, and hence to identify those patients more
© European Society for Human Reproduction and Embryology
likely to conceive. Simonet al. (1993) compared women who
conceived naturally with those who conceived in a previous
IVF cycle. The numbers were small and male factor infertility
was excluded, making comparisons less valid. However, a
previously successful IVF cycle did offer an improved
prognosis in comparison to those who had previously conceived
naturally.
Certain factors have been shown to affect conception rate,
e.g. age (Tan et al., 1992). The aetiology of infertility ought
to affect the success of IVF especially if sperm dysfunction
decreases the fertilization rate. Intracytoplasmic sperm injection (ICSI) has now altered the odds for these couples but in
this study none of the patients underwent this treatment which
had only recently become available within the unit.
Many women are now having repeated IVF treatment cycles
and want to know whether their chances of conceiving increase
with an increasing number of attempts. This can be best
assessed by evaluating the cumulative pregnancy rate, helping
a couple to plan how many cycles to undergo. Cumulative
pregnancy rates also enable the comparison of IVF results
between units. Few centres have produced such information;
those that have done so have analysed relatively few cycles.
Other problems with published data are that reports frequently
include heterogeneous techniques, with gamete intra-Fallopian
transfer (GIFT), IVF and frozen replacement cycles all considered in the same series. Moreover, many reports have analysed
pregnancy rates only after embryo transfer or oocyte retrieval,
thus excluding cycles where fertilization has failed or the cycle
was abandoned before attempts at oocyte retrieval.
Matrials and methods
A total of 9316 cycles were commenced at the Hammersmith and
Royal Masonic Hospitals between 1988 and 1995. All these couples
were treated using one standard treatment protocol, with the same
clinical and embryological team involved in all treatments. The only
difference between the two hospitals was that the majority of patients
at The Hammersmith were in the public sector whereas those at The
Royal Masonic were largely treated on a fee-paying private basis.
Recent data from the Human Fertilisation and Embryo Authority
(1996) show that the success rates, measured as live births per
treatment cycle, at both these centres are identical.
During ovulation induction all patients were treated using a standard
protocol (Rutherford et al., 1988) for pituitary desensitization with
150 mg/daily of a gonadotrophin agonist (buserelin; Hoechst,
Hounslow, Middlesex, UK) administered from the second day after
menstruation commenced. When complete ovarian suppression was
observed (serum oestradiol concentration <80 pmol/l and no follicles
seen on ultrasound), the ovaries were stimulated with human menopausal gonadotrophin (HMG; Pergonal, Metrodin: Serono Labora-
403
C.A.Croucher et al.
Table I. Correlation between patient age and pregnancy rate in a first in-vitro fertilization attempt
Age
(years)
No. of
cycles
Cancelled
cycles (%)•
No. of
pregnancies
Pregnancy
rate per cycleb
No. of
miscarriages (% )c
20-25
26-30
31-35
36-40
;;,41
Total
89
939
2089
1632
324
5073
8
129
331
350
128
946
43
311
597
348
25
1324
48.3
33.1
28.6
21.3
7.7
26.1
3
37
73
52
5
170
(12.0)
(13.7)
(15.8)
(21.4)
(39.5)
(18.6)
(7.0)
(11.9)
(12.2)
(14.9)
(20.0)
(12.8)
•cancellation rate is higher in women >35 years old (P < 0.001).
bPregnancy rate drops with increasing age (P < 0.01 between each age group).
cThere is no significant difference in miscarriage rates between the age groups ..
Table II. Relationship between patient age and ovulation induction response
Age
(years)
No. of
ampoules
ofHMG
Serum
oestradiol
concentration
(pmol/1)
Days of
HMG
No. of
oocytes
retrieved
No. of
oocytes
fertilized
20-25
26-30
31-35
36-40
;;,41
29.5
31.6
35.6
46.3
61.1
7376
6961
6625
6418
5736
12.9
13.2
13.1
13
13.5
12.3
10.9
9.6
9.4
6.9
6.6
6.0
5.2
4.5
3.5
HMG = human menopausal gonadotrophin.
Differences were statistically significant (P < 0.01) between all age groups and parameters except for
HMG dosage and peak oestradiol between the 20-25 and 26-30 year age groups.
tories, Welwyn, Herts, UK; or Humegon, Orgafol, Normegon; Organon
Laboratories Ltd, Cambridge, UK). Ovarian response was monitored
daily with serum oestradiol assays and vaginal ultrasound. When at
least three follicles ? 17 mm in diameter were observed and oestradiol
levels had reached 3000 pmol/1, a triggering dose of lO 000 IU of
human chorionic gonadotrophin (HCG, Profasi; Serono) was given
i.m. Cycles were cancelled if these criteria for follicular development
were not reached. Egg collection was undertaken by transvaginal
aspiration -34 h after HCG injection. After fertilization under
standardized culture conditions, embryo transfer was performed 2 or
3 days later. Embryos were transferred on day 3 after a Friday
collection to avoid embryo transfer on Sundays. In nearly all cases
only two embryos were transferred per cycle. On rare occasions,
when IVF had already failed repeatedly or when the prognosis was
considered to be particularly bad, three embryos were transferred.
Luteal support was with pure progesterone in oil (25 mg i.m. injection)
three times daily for the first 3 days and then with a single injection
once daily for 2 days. Thereafter progesterone pessaries (200 mg)
were given daily for lO days. Pregnancy was diagnosed by measuring
serum ~HCG 12-16 days after embryo transfer.
A pregnancy was defined as a rise in ~HCG on day 14 after oocyte
retrieval, together with evidence of a gestational sac seen on ultrasound
after a further 2 weeks. Biochemical pregnancy was defined as a
transient rise in serum ~HCG to >20 IU/ml on day 14 after
oocyte retrieval.
The age and cause of infertility was recorded in each case. We
also compared the outcome of a subsequent IVF cycle to see if
women who had already been successful had a better prognosis. The
prognosis in those who had had a biochemical pregnancy or in those
whose first cycle had been cancelled due to poor response to ovarian
stimulation was also evaluated. The cumulative pregnancy rate was
calculated for repeat attenders using life tables. The cumulative rate
included all cycles up to the first pregnancy.
404
Statistics
x2-Test and the Student's t-test for unpaired data were used to test
for the significance of any differences (P < 0.05) on the Stat View
statistical package (Abacus Concepts Inc., Berkeley, CA, USA). In
addition, using life table analysis (Peto et al., 1977), a cumulative
pregnancy rate as a percentage for repeat attenders was calculated
(Kovacs et al., 1986) using the formula:
cumulative pregnancy rate
=
P%
=
(100- S)
+ (SXP)/100
where S is the percentage of women who were not pregnant at the
start of the cycle.
Results
A total of 5073 first cycles were started, of which 4121 went
to oocyte retrieval (OR). Of these cycles, 1325 (26% per cycle
commenced; 32% per OR) resulted in a clinical pregnancy.
Subsequently 2396 patients underwent a further IVF attempt.
The cause of infertility had no bearing on outcome. However,
the age of the female partner was highly significant. A
difference of only 5 years had an influence on outcome in
each of the age ranges studied. The miscarriage rate also
increased with age but no statistical difference was recorded
(Table I).
With increasing age, significantly more HMG was required
to produce an adequate response. Moreover, older women
produced fewer eggs (Table II). This was irrespective of
whether this was a first cycle.
Women who had more than one cycle of IVF needed more
HMG and in spite of this yielded fewer eggs. The mean
number of eggs collected in a first cycle was 9.4 requiring 39
Prredlctive value of lksC IVF ;:ydc results
Table HI. Comparison between patients who did not conceive in their first
cycle and returned for a second attempt and those who chose not to return
No. of patients
Age (years)
No. of HMG ampoules
Days ofHMG
Peak oestradiol (pmol/1)
No. of oocytes recovered
No. of oocytes fertilized
No. of embryos transferred
Returned for 2nd cycle
Did not return
1125
34.5
42.4
13.1
6589
9.1
4.4
1.8
1923
33.9
39.7
13.3
6519
9.2
± 4.3
± 20.9
± 2.9
± 3335
± 4.7
± 3.5
± 0.9
± 4.1
± 20.1
± 3.1
± 2368
± 4.6
4.9 ± 3.5
1.9 ± 0.9
Values are mean ± SD. No significant difference between the groups.
HMG = human menopausal gonadotrophin.
ampoules of HMG. In a second cycle 47 ampoules produced
8.7 eggs and in a third cycle 52 ampoules were needed to
produce 8.7 eggs. The difference in the amount of HMG
required was significant (P < 0.001), as was the difference
between the number of eggs collected in the first and second
cycles
< 0.001). There was no difference in the length of
time that HMG was given
12.9 ± 3.0 days) or in
fertilization rates.
Only 2396 women (47.2%) returned for a subsequent cycle.
Of these, 1125 had not conceived at their first attempt. We
found no clinical difference in those women returning for a
subsequent treatment cycle, nor was there any evidence of
specific factors influencing return for a third or fourth treatment
attempt (Table III).
The results after a second IVF cycle, shown in Table IV,
demonstrate a significant increase in pregnancy rate in women
experiencing a clinical (32.5%) or biochemical (36.4%)
pregnancy in a first cycle compared to those whose first cycle
was cancelled ( 19.5%) or yielded a negative result despite
reaching oocyte retrieval (23.6%). Table V shows that the
pregnancy rates among those whose first cycle produced a live
infant (32.5%) or ended in miscarriage (31.5%) were similar.
In our study, of the 26 women who had an ectopic pregnancy
in their first cycle and ventured further treatment, six (23%)
subsequently conceived a normal pregnancy in their second
cycle. Despite the small numbers this finding supports the
view of Karande et al. (1991) whose patients had a good
chance of a normal pregnancy with subsequent IVF. In their
study, 3.3% of pregnancies were ectopic. We found that only
one of 26 (3.8%) women previously experiencing an ectopic
IVF pregnancy had a second ectopic. The incidence of
pregnancy is higher among those with tubal disease as the
cause of their infertility, possibly because embryos are regurgitated into a damaged tube after transfer. Of those women who
had an ectopic pregnancy in their first
25
had
tubal disease as their cause of infertility. In all IVF patients
with tubal disease, there should be an awareness of the
possibility of ectopic pregnancy.
Table VI shows the cumulative pregnancy rate after all
cycles. Figure 1 shows the cumulative pregnancy rate per cycle
and per retlieval up to six cycles. The seventh and subsequent
attempts were not included due to the small number of patients
involved.
Discussion
To our knowledge this is the first
of cumulative pregnancy
rate after IVF in a
with one team of
and clinical staff and the most effective ovulation
protocol available. This
of
the
hormone
longer period,
because of poor ovarian response or
LH. Abolition of spontaneous LH surges al.so has the
of permitting
oocyte collection. Tan
showed an
and Jive birth rate
with this approach.
Age is the most
the outcome of IVF
(Bopp et al., 1995). In our
women
age group with a 48% pregnancy rate are at an
over
those aged ;341 yem:s who had an 8% chance
This seems in part to be due to a
ovulation induction. In
of increased
older women
fewer oocytes and had a
cancellation rate. However, the fertilization rate of their
remained
constant, suggesting that oocyte
may
clecrease very
much with age.
It is widely believed that
who discontinue IVF after
a failed attempt do so because
have a
We found little evidence for this view. When we
the aetiology, age, ovarian response and fertilization rate of
those who retumed
those who did not, we found no
difference
outcome. This
that
were not dissuaded from
It is inevitable that some
immeasurable, inherent bias exists between
who
assisted
versus those who
continue. If motivation were to influence outcome with
'quitters'
a poorer
obviously be biased towards those
do couples not persevere with treatment? Of those not
returning, 39.2% became
in their first
After
successful pregnancy many women decided not to
with further treatment; hmuP'•'"'"''
return if a pregnancy test had been
had been born. The number of women
many
is low.
some
transfer to other centres
because of dissatisfaction. Others discontinue treatment
because
than
Many
consideration with such
treatment.
The cause of
even when two or
were
did not affect IVF outcome. Unlike
of Toumaye et al.
we did not find
nrale factor
infertility was associated with lower pregnancy rates
One of the
of IVF
its
fertilization disorders. When there was fertilization failure in
normozoosperm ic men at a first IVF
1991), the
still
with an
outcome.
Gabrielsen et al.
failure of fertilization with normal spenr1
be alleviated
ICSI in future aw~lH.UL
405
C.A.Croucher et al.
Table IV. Outcome of a second in-vitro fertilization attempt in patients who were pregnant in their first
cycle, had biochemical pregnancy, did not conceive or their cycle was cancelled
First cycle outcomes
Pregnant
Biochemical
Not pregnant"
Cancelled•
No. of patients having
second cycle
No. of pregnancies(%)
Deliveries (% )c
Miscarriages (% )c
Ectopic pregnancies (%)c
Lost to follow-up (% )c
Others
317
129
1387
563
328 (23.6)
239 (72.9)
54 (16.5)
6 (1.8)
26 (7.9)
2 stillbirths
nob (19.5)
71 (64.5)
14 (12.7)
I (1.0)
5 (4.5)
I termination
I neonatal death
13%
Live birth rate
103 (32.5)
73 (70.9)
19 (18.4)
5 (4.8)
4 (3.9)
2 terminations
47
33
8
5
(36.4)
(70.2)
(17.0)
(10.6)
I (2.1)
26%
23%
17%
•Pregnancy and live birth rates are significantly lower (P < 0.01) in the non-pregnant and/or the cancelled
cycle, compared to the pregnant and/or the biochemical in the first cycle.
bDefined as an ongoing pregnancy at the unit's last contact date with the patient at 10, 12 or 20 weeks
gestation. In some cases birth details were unknown.
cThe percentages are based on the number of pregnancies.
Table V. Outcome of a second cycle after a pregnancy in the first in-vitro
fertilization (IVF) cycle
1st cycle outcome
Delivered in
1st IVF
Miscarried in
1st IVF
Ectopic in
1st IVF
No. of patients having
a second cycle
No. of pregnancies(%)
Live births (% )b
Miscarriages (% )b
Ectopic pregnancies (% )b
Lost to follow-up (%)b
Biochemical
pregnancies (% )c
Others
166
111
26a
56
42
7
2
4
2
(32.5)
(75)
(12.5)
(3.6)
(7.1)
(1.2)
35 (31.5)
23 (65.7)
9 (25.7)
I (2.9)
1 (2.9)
6 (5.4)
1 termination
6a (23.1)
3 (50.0)
2 (33.3)
1 (16.7)
1 (3.8)
1 termination
IVF= in-vitro fertilization.
•Includes pregnancies defined as ongoing because a fetal heart was detected
at 10, 12 or 20 weeks gestation but whose final outcome is unknown.
bThe percentages are from the number of pregnancies.
cThe percentages are from the number of cycles.
There were no statistical differences between the three groups.
90
~
.."...
80
~
70
.=."
60
"
::::
50
"a
"",..
;:;"
e
"
40
u
Cumulative pregnancy rate(%) PerO.R cycles
Cwnulative pregnancy rate (%) per starting cycles
30
20
3
4
Cycle number
Figure 1. The cumulative pregnancy rate per started cycle and per
oocyte retrieval (OR) up to six cycles. Results are expressed as
mean ± SEM. Seventh and subsequent attempts were excluded
because of low numbers.
406
Couples who have previously achieved an IVF pregnancy
have a significantly better prognosis in a subsequent IVF cycle
(33%) compared to those not conceiving (24%; P = 0.001).
A 24% pregnancy rate in those with a prior failure is still
clinically acceptable. Although a previous miscarriage in an
IVF-pregnancy appeared to be associated with a possibly
increased risk of miscarriage in a subsequent pregnancy,
the difference was not statistically significant. The overall
miscarriage rate was 3% in the 20--25 year age group and
20% in those >40 years old, but again, this increase was not
statistically significant. The rate in the >40 year age group
was much lower than the 50% reported by Padilla and Garcia
(1989). Tan et al. (1994b) also concluded that women with a
previous IVF pregnancy had a higher cumulative conception
rate than couples in their first IVF cycle. However, they
used six different stimulatory regimes, which makes valid
comparison difficult.
A prior biochemical pregnancy was a significant, favourable
indicator. Our patients had a clinical pregnancy rate of 36.4%
in second cycles following a biochemical pregnancy in the
first cycle. This is similar to the chance of pregnancy (32.5%)
after a clinical pregnancy. Molloy et al. (1995) also concluded
that previous biochemical pregnancy was a good prognostic
feature. However, they studied a heterogeneous group of
treatments using either frozen embryo replacement, GIFT or
routine IVF alone to gather sufficient data. They also found
that second and third IVF attempts had a better outcome
among their 784 women who returned after having had a child .
They studied the outcome in fewer patients, and accurate
comparison between successful and unsuccessful treatment
was not possible. We do not know the reason for the favourable
influence of a pregnancy upon a subsequent attempt. This may
be due to embryological or endometrial response, or perhaps
a combination of the two, and requires further investigation.
Biochemical pregnancy may provide useful information. In
normal fertile, ovulatory women there is considerable evidence
(Miller et al., 1980; Wilcox et al., 1988) that early pregnancy
loss happens frequently. The fact that HCG rises, however
transiently, indicates that the embryo was sufficiently well
Predictive value of first IVF cycle results
Table VI. Pregnancy rate and cumulative pregnancy rate (per cycle)
Cycle
number
No. of
patients in
cumulative
data
No. of
pregnancies
in cumulative
data
Pregnancy
rate(%)
Cumulative
pregnancy
rate(%)
SE of
cumulative
pregnancy
rate
Total no. of
patients per
cycle
Total no. of
pregnancies
Pregnancy
rate per
cycle(%)
1
2
3
4
5
6
7
5073
2078
784
319
117
39
11
1325
477
148
43
23
5
3
26.1
23.0
18.9
13.5
19.7
12.8
27.3
26.1
43.1
53.9
60.1
68.0
72.1
79.7
0.5
0.8
1.2
1.7
2.4
3.8
5.5
5073
2396
1065
480
193
77
22
1325
588
246
83
36
11
5
26.1
24.5
23.1
17.3
18.7
14.3
22.7
The pregnancy rate in each of the first three cycles was the same. In the forth and subsequent attempts the pregnancy rate was significantly decreased
(P < 0.0001).
developed to implant. Embryo quality as measured by morphological appearance was shown to be no different after IVF
given an ongoing pregnancy or a biochemical pregnancy (Levy
et al., 1991). However, it was less good in cycles which gave
rise to an abortion.
The chance of pregnancy after a single IVF cycle (26%) is
similar or better than the chance of conception in 1 month of
normal intercourse in a normal fertile population (Sharp et al.,
1986) and remains constant for the first three attempts at our
unit. This point has major implications for the National Health
Service when health authorities make purchasing decisions
concerning IVF. Templeton's data (1996) differed from these
findings and showed a decreased success rate with each IVF
cycle. However, multiple treatment regimes from different
centres can distort real trends within individual units, especially
during a short study period. In the UK, the cumulative
probability of pregnancy is 32% after 3 months of intercourse.
After three IVF cycles the pregnancy rate per cycle does
decline, as does the number of patients, but the chance of
pregnancy remains 17-23%. A cumulative pregnancy rate of
80% after seven cycles is encouraging despite the small
numbers undergoing repeated cycles. We found the cumulative
pregnancy rate to be 54% after three cycles and 72% after six,
compared with nearly 55% after 6 months in a normally
cohabitating, fertile population.
Of the 5073 patients who underwent their first cycle at our
unit, some had undergone a prior IVF attempt elsewhere.
These cycles would have consisted of different protocols and
were therefore not taken into account. However, this could
adversely affect our pregnancy rates if poorer responders from
elsewhere were inclined to try a different unit. Alternatively
a favourable bias would result from couples who had previously
conceived with another team.
Unlike Guzick et al. (1986) who reported the probability of
pregnancy remaining constant throughout successive cycles,
we found an equal probability in the first three cycles followed
by a significantly reduced chance. An early study by Kovacs
et al. (1986) reported constant pregnancy rates in up to eight
cycles. These authors concluded that, provided patients were
prepared to undergo several IVF cycles, their clinical success
rates rose to 49% after five egg collections. Dor and colleagues
(1996) showed a constant increase in cumulative pregnancy
rate which reached a plateau of 56% after six cycles. This was
a small series and used three different protocols, so that
unbiased comparisons are impossible. Two groups of patients
undergoing IVF were considered by Simon et al. (1993). The
first group had previously conceived with IVF and the second
had previously conceived naturally. Those who conceived
naturally, but were subsequently infertile, were less likely to
achieve a pregnancy than those who had initially conceived
with IVF. Possibly these successful women had a better
endometrial response or were less susceptible to any deleterious
effects on their eggs or uterus occurring during gonadotrophin
stimulation.
To conclude, IVF treatment should not be seen as an isolated
event, and biochemical and failed clinical pregnancy should
be viewed with a degree of cautious optimism. All couples
undergoing IVF treatment should consider that this implies a
course of three or more treatment cycles with equal chances
of pregnancy in each cycle. The probabilities of success are
somewhat higher than those after natural intercourse. Beyond
three cycles, success rates per cycle fall, though cumulative
pregnancy rates continue to rise, albeit at a slower rates and
the chances are still sufficiently high to encourage those
with sufficient resources and commitment to try three more.
Although it is impossible to predict accurately those who are
likely to have a child, analysis of the cumulative pregnancy
rate from a treatment centre provides useful information in
making decisions about IVF treatment.
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Received on May 1, 1997; accepted on October 28, 1997
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