IN VITRO FERTILIZATION
Egg production predicts a doubling of in vitro
fertilization pregnancy rates even within defined age
and ovarian reserve categories
Melissa C. Yih, M.D., Steven D. Spandorfer, M.D., and Zev Rosenwaks, M.D.
The Center for Reproductive Medicine and Infertility–Weill Medical College of Cornell University, New York, New York
Objective: To examine the age-independent association of ovarian response and IVF outcome in women with
normal and abnormal ovarian reserve.
Design: Retrospective analysis.
Setting: Academic IVF center.
Patient(s): Four thousand eight hundred sixty-two consecutive IVF cycles.
Intervention(s): None.
Main Outcome Measure(s): Outcome of IVF was analyzed as a function of ovarian response to controlled ovarian
hyperstimulation and ovarian reserve.
Result(s): The mean patient age was 36.2 ⫾ 4.5 years. Younger patients and patients with normal ovarian reserve
were found to have better implantation and clinical pregnancy rates. Patients with normal ovarian reserve had a
higher number of oocytes retrieved, mature oocytes, two-pronuclei embryos, and embryos transferred. A greater
number of embryos were transferred for patients with higher ovarian response. Higher clinical pregnancy rates
were seen in those patients who had more oocytes retrieved for all patients, regardless of age and ovarian reserve.
In fact, clinical pregnancy rates more than doubled for specific patient groups.
Conclusion(s): In an age-independent fashion, ovarian response is highly predictive of IVF outcome in women
with normal and abnormal ovarian reserve. These findings highlight the importance of not solely relying on age
when presenting and discussing IVF outcome data and are useful information when helping patients interpret their
IVF cycle response. (Fertil Steril威 2005;83:24 –9. ©2005 by American Society for Reproductive Medicine.)
Key Words: IVF outcome, ovarian response, age independent
Maternal age is the major determinant in predicting IVF outcome. Fecundity decreases with advancing maternal age (1, 2).
This decline is also reflected in older women undergoing assisted reproduction, such as IVF (3). In addition, IVF success is
modified by ovarian reserve. Elevated FSH levels have been
associated with poor performance during IVF and are a reflection of a diminished ovarian reserve (4).
Ovarian response has also been suggested as a predictor of
IVF treatment (4). Patients who have a good response to
controlled ovarian hyperstimulation (COH) have been found
to have a better prognosis for IVF treatment. One previous
study has suggested that a cutoff of fewer than three follicles
during ovarian stimulation should be used as a guideline for
cycle cancellation (6). It has been proposed that response to
Received July 4, 2002; revised and accepted May 10, 2004.
Presented at the Annual Meeting of the American Society for Reproductive Medicine, Orlando, Florida, October 17, 2001.
Reprint requests: Melissa Yih, M.D., IVF New Jersey, 3100 Princeton Pike,
Bldg. 4, Suite I, Lawrenceville, NJ 08648 (FAX: 609-219-0742; E-mail:
[email protected]).
24
COH may be used independently to predict successful IVF
outcome.
In this study, we attempted to define how ovarian response
coupled with ovarian reserve can predict age-independent
IVF outcome in a large cohort of patients.
MATERIALS AND METHODS
From 1996 to 2000, 4,862 consecutive IVF cycles from The
Center of Reproductive Medicine and Infertility at the Weill
Medical College of Cornell were retrospectively reviewed.
The study was approved by the Institutional Ethics and
Research Committee.
Cycles using donor oocytes, transfer of frozen embryos,
natural cycle, experimental protocols, or blastocysts were
excluded. On the basis of day 3 FSH levels, patients were
labeled as having either normal or poor ovarian reserve. By
using an RIA (Quantitative FSH Assay; Solid Phase Inc.,
Portland, ME), a cutoff of 20 mIU/mL was considered as an
indicator of abnormal ovarian reserve. Normal ovarian reserve patients were those patients who had a day 3 FSH level
Fertility and Sterility姞 Vol. 83, No. 1, January 2005
Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/05/$30.00
doi:10.1016/j.fertnstert.2004.05.096
of ⬍20 mIU/mL. Poor ovarian reserve patients were defined
as those patients who had a day 3 FSH level of 20 –22
mIU/mL and/or a day 3 estradiol (E2) level of ⬎70 pg/mL
and/or who had a history of poor response in previous
protocols (i.e., estrogen levels ⬍500 pg/mL, follicle numbers ⱕ3).
FIGURE 1
Distribution of patients with normal vs. poor
ovarian reserve, by maternal age (y). Blue bars,
normal ovarian reserve. Yellow bars, poor ovarian
reserve.
At our center, patients with an FSH of ⬎ 22 mIU/mL had
a pregnancy rate close to 0, and hence this number has been
used as our cutoff for IVF treatment.
An IVF cycle was canceled if no more than five follicles
were present, and E2 level was ⬍1,000 pg/mL.
Normal ovarian reserve patients were treated with a standard ovulation induction protocol and underwent IVF as
described elsewhere (7). In brief, patients were started with
luteal phase leuprolide acetate (GnRH-a, Lupron; TAP Pharmaceuticals, Deerfield, IL; 0.5–1 mg SC daily) until ovarian
suppression was achieved. Poor ovarian reserve patients
began stimulation on day 2 of their treatment cycle. These
patients were placed on a flare based, clomiphene citrate
based, or no-lupron protocol.
For both normal and poor ovarian reserve patients, ovarian
stimulation was effected with a combination of gonadotropins (hMG) and/or FSH; Pergonal or Metrodin; Serono,
Waltham, MA), employing a step-down protocol. Human
chorionic gonadotropin (3,300 to 10,000 IU) was administered when at least two follicles of 17-mm diameter were
observed by transvaginal ultrasound. Oocytes were harvested by transvaginal ultrasound-guided follicular puncture
approximately 35 hours after hCG administration.
Conventional oocyte insemination or micromanipulation
was performed as indicated. Morphologically normal embryos were transferred into the uterine cavity approximately
72-hours after retrieval. As per our standard protocol, the
number of embryos transferred was dependent on maternal
age. In general, women under 34 years of age, between 35 to
39 years, and aged 40 years and over underwent a transfer of
three, four, and five embryos, respectively.
Methylprednisolone (16 mg/d) and tetracycline (250 mg
every 6 hours) were administered for 4 days to all patients,
commencing on the day of oocyte retrieval. Progesterone
supplementation was initiated on the 3rd day after hCG
administration (25–50 mg IM daily) and was continued until
sonographic assessment of the pregnancy at 47–51 days of
gestation, as determined by the day of oocyte insemination
(day 14).
Data were collected regarding outcome of IVF cycle. A
clinical pregnancy was defined as the presence of a fetal
heartbeat at the 7-week sonogram. Implantation rate was
defined as number of fetal hearts per the number of embryos
transferred.
Patient data is analyzed with respect to maternal age,
ovarian reserve, and number of oocytes at the time of retrieval. Data is collected using the Stat View program. ChiFertility and Sterility姞
Yih. Egg production predicts IVF pregnancy rates. Fertil Steril 2005.
square analysis and nonparametric t tests were performed. A
P value of ⬍.05 was considered significant.
RESULTS
Four thousand eight hundred sixty-two consecutive IVF cycles were studied over a 4-year period (1996 –2000). The
mean (⫾ SD) maternal age was 36.3 (⫾4.5) years. Overall,
clinical pregnancy rate per retrieval and implantation rate per
retrieval were 46.9% and 22.1%, respectively.
Effect of Age
Maternal age was found to be an important factor in predicting implantation and clinical pregnancy rates. Younger patients had significantly higher implantation and clinical pregnancy rates (for patients aged ⬍34, 34 –39, 40 – 41, and ⱖ42
years of age, the implantation rates were 33.7%, 22.2%,
12.2%, and 6.3%, and the clinical pregnancy rates were
58.2%, 48.9%, 39.5%, and 25.7%, respectively; P⬍.0001).
Effect of Ovarian Reserve
Eighty percent (3,881 of 4,862 patients) of the total number
of patients were defined as having normal ovarian reserve,
whereas 20% (981 of 4,862 patients) had poor ovarian reserve. Patients with a normal ovarian reserve were younger
than patients with an abnormal ovarian reserve (35.6 ⫾ 4.5
vs. 38.7 ⫾ 3.8 years, P⬍.0001). Not surprisingly, as maternal age increased, the percentage of patients with poor ovarian reserve also increased (See Fig. 1). Patients with a
25
TABLE 1
Normal vs. poor ovarian reserve characteristics.
Variable
Normal ovarian
reserve
(n ⴝ 3,881)
Poor ovarian
reserve
(n ⴝ 981)
35.6 ⫾ 4.5
12.2 ⫾ 5.7
9.9 ⫾ 4.9
7.2 ⫾ 4.2
3.4 ⫾ 1.3
38.7 ⫾ 3.8
6.6 ⫾ 4.0
5.5 ⫾ 3.5
3.9 ⫾ 2.9
2.9 ⫾ 1.6
34.1
24.2
13.3
7.9
27.6
13.9
9.5
4
NS
⬍.0001
.006
.001
59.1
53.8
44.4
32.1
45.2
29.3
26.8
31.6
.01
⬍.0001
⬍.0001
⬍.0001
Age (y)
No. of oocytes retrieved
Mature oocytes
2PN
ET
Implantation rate (%)
⬍34
34–39
40–41
ⱖ42
Clinical pregnancy rate (%)
⬍34
34–39
40–41
ⱖ42
P value
.0001
.0001
.0001
.0001
.0001
Note: Data are mean ⫾ SD. NS ⫽ not statistically significant; 2PN ⫽ two pronuclei.
Yih. Egg production predicts IVF pregnancy rates. Fertil Steril 2005.
normal ovarian reserve had a better stimulation response and
IVF outcome (see Table 1) than did patients with poor
ovarian reserve.
significantly higher number of embryos were transferred for
patients with a higher ovarian response (see Table 2). Additionally, ovarian response was associated with clinical
pregnancy rate. This was more dramatically seen in patients
with normal ovarian reserve (see Table 3).
Effect of Ovarian Response
To more effectively assess ovarian response, we stratified the
data to control for both maternal age and ovarian reserve. A
A correlation between implantation rates and ovarian response was also found. A significantly higher implantation
TABLE 2
Coupling of ovarian reserve and ovarian response and its effect on number of embryos transferred.
Embryos transferred
n
≤4 Oocytes
retrieved
(n ⴝ 525)
ⱕ33
34–39
40–41
⬎42
1,271
1,787
471
352
1.6
2.0
1.9
2.1
ⱕ33
34–39
40–41
⬎42
85
454
179
263
1.6
1.7
1.6
1.8
Age
(y)
5–7 Oocytes
retrieved
(n ⴝ 916)
Normal ovarian reserve
2.5
3.0
3.5
3.4
Poor ovarian reserve
2.6
3.1
3.3
3.1
≥8 Oocytes
retrieved
(n ⴝ 3,421)
P value
2.9
3.6
4.4
5.0
⬍.0001
⬍.0001
⬍.0001
⬍.0001
2.9
3.7
4.1
4.9
.0012
⬍.0001
⬍.0001
⬍.0001
Yih. Egg production predicts IVF pregnancy rates. Fertil Steril 2005.
26
Yih et al.
Egg production predicts IVF pregnancy rates
Vol. 83, No. 1, January 2005
TABLE 3
Coupling of ovarian reserve and ovarian response and effect on clinical pregnancy rate.
Clinical pregnancy rates (%)
n
≤4 Oocytes
retrieved
(n ⴝ 525)
ⱕ33
34–39
40–41
⬎42
1,271
1,787
471
352
37.5
23.9
18.4
11.8
ⱕ33
34–39
40–41
⬎42
85
454
179
263
33.3
17.7
15.5
11.1
Age
(y)
5–7 Oocytes
retrieved
(n ⴝ 916)
Normal ovarian reserve
52.0
44.7
28.9
24.7
Poor ovarian reserve
45.5
31.1
32.8
19.8
≥8 Oocytes
retrieved
(n ⴝ 3421)
P value
60.7
57.6
51.8
37.1
⬍.003
⬍.0001
⬍.0001
⬍.004
48.9
39.3
31.7
22.1
.58
⬍.0002
⬍.05
.12
Yih. Egg production predicts IVF pregnancy rates. Fertil Steril 2005.
rate was seen in women between 34 – 41 years of age who
had a better ovarian response. Interestingly, younger patients
(ⱕ33 years) with normal ovarian reserve still maintained
very high implantation rates despite a poor ovarian response
(ⱕ4 oocytes; see Table 4). Implantation rates were not
significantly different for patients with poor ovarian reserve
based upon ovarian response.
DISCUSSION
Maternal age is the most reliable predictor of IVF success.
Compared with younger patients, women older than 40 years
of age have fewer successful IVF cycles. Implantation, preg-
nancy and delivery rates in older women are routinely lower
than those of younger women undergoing IVF (8, 9). This
decline in success is a reflection of a decline in embryo and
oocyte quality, as seen by significantly better pregnancy
rates in ovum recipient (10, 11).
Ovarian reserve testing is also commonly used to predict
IVF success. Testing includes day 3 FSH ⫾ E2 levels (12),
the clomiphene citrate challenge test (13), measurements of
ovarian volume (14), and intraovarian blood flow (15). Day
3 FSH ⫾ E2 levels are the most widely used of these tests.
In our clinic, women with an FSH level ⱖ20 mIU/mL have
a significantly lower implantation rate and a greater chance
TABLE 4
Coupling of ovarian reserve and ovarian response and the effect on implantation rates.
Implantation rates (%)
n
≤4 Oocytes
retrieved
(n ⴝ 525)
ⱕ33
34–39
40–41
⬎42
1,271
1,787
471
352
29.0
13.0
6.4
5.7
ⱕ 33
34–39
40–41
⬎42
85
454
179
263
31.8
13.8
9.2
4.0
Age
(y)
5–7 Oocytes
retrieved
(n ⴝ 916)
Normal ovarian reserve
31.5
19.3
8.8
8.1
Poor ovarian reserve
20.5
11.8
9.9
4.3
≥8 Oocytes
retrieved
(n ⴝ 3,421)
P value
34.6
25.8
15.2
8.1
.44
.0001
.0012
.21
30.0
15.9
9.3
3.6
.83
.19
.21
.74
Yih. Egg production predicts IVF pregnancy rates. Fertil Steril 2005.
Fertility and Sterility姞
27
of having their IVF cycle canceled for poor response as
compared with women with an FSH level of ⬍20 mIU/mL.
Today in most clinics, the more conventional immunolyte
assay is used and uses an FSH cutoff of 10 mIU/mL to define
normal ovarian reserve.
Although ovarian responsiveness is not known until after
an IVF cycle has been undertaken, it recently has been used
to predict success rates. Alrayyes et al. (16) examined the
effect of cycle responsiveness on IVF outcomes in patients
with male infertility. Specifically, the number of embryos
transferred was used as a reflection of ovarian response.
When comparing high responders (⬎3 embryos transferred,
with a mean number of 15.1 oocytes retrieved) to those
patients with a lower response (ⱕ3 embryos transferred with
a mean number of 5.6 oocytes retrieved), fertilization rates,
implantation rates, and number of clinical pregnancies were
significantly higher in those patients who had a higher ovarian response.
Silber et al. (17) also revealed that ovarian response is an
important predictor of IVF success. They examined the
effect of ovarian response on delivered pregnancy rates in
patients with male infertility. The number of eggs retrieved
did not significantly affect the two-pronuclei fertilization and
the cleavage rate. However, the number of eggs retrieved
significantly affected the delivered pregnancy rate. For
women who had more than eight eggs retrieved, the delivered pregnancy rate was more than twofold higher (36% vs.
14%). Even when controlled for age, women who produced
at least nine eggs had an average of almost twice the pregnancy rate compared with women who produced less than
nine eggs. Because the number of embryos transferred was
no different between the two groups, egg quality was felt to
be responsible for the higher pregnancy rates.
More recently, Biljan et al. (18) examined the outcome of
IVF in patients who developed three follicles or less during
controlled ovarian hyperstimulation. Outcomes of patients
who developed no more than three follicles vs. more than
three follicles were compared. Older patients had a fivefold
greater chance of having poor follicular recruitment and a
threefold lower chance of achieving pregnancy. The number
of follicles recruited had different implications in patients
who were younger vs. in those who were older. For women
aged younger than 40 years, no significant difference in the
quality of embryos transferred or in the pregnancy and live
birth rates for women who had no more than three vs. more
than three follicles was found. A higher multiple pregnancy
rate in the group with more than three follicles was found,
though. In women older than the age of 40 years, although
fertilization rates did not differ, the number and quality of
embryos transferred were lower in the group of poor responders. For patients who were able to produce more than
three follicles, a better choice of embryos at the time of
transfer and replacement of more embryos resulted in a
cumulative embryo score similar to those achieved in
younger good responders. Hence, in this group, age older
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Yih et al.
Egg production predicts IVF pregnancy rates
than 40 years played a moderate role in the chances of
achieving pregnancy, and ovarian response appeared to be a
more significant variable.
This study confirms that ovarian response is an independent variable, which can predict clinical pregnancy rates
irrespective of age and ovarian reserve. We were able to
illustrate that depending on the number of oocytes retrieved,
there was a significant difference in the number of embryos
transferred and clinical pregnancy rates for the majority of
patients. In fact, pregnancy rates more than doubled for
certain categories depending on ovarian response.
A significant difference in clinical pregnancy rates for
poor ovarian reserve patients was not seen in women who
were ⱕ33 years of age and those who were ⱖ42 years of
age. In the former category, the number of patients ⱕ33
years of age with poor ovarian reserve was quite small (n ⫽
85); hence, there may not have been enough patients to show
a difference. Furthermore, the clinical pregnancy rate was
quite high to begin with. For patients who were ⱖ42 years of
age, the clinical pregnancy rate was double in women who
had at least eight oocytes versus those who produced no
more than four.
The information gathered in this study is useful in many
ways. First, it illustrates that whereas maternal age is an
important predictor of IVF success, other factors such as
ovarian response also play a role in predicting IVF success
rates. One way to explain our findings is that despite the fact
that ovarian reserve and embryo quality decrease with advancing maternal age, if enough oocytes are produced and
hence embryos, the selection of embryos for transfer is
improved and allows for transfer of the best embryos back to
the patient. Second, this study provides valuable information
when counseling patients regarding cycle response and expected pregnancy rates for future cycles. For example, when
speaking of IVF success, patients should be counseled that
although maternal age is important, cycle response also plays
a role. With this information, patients who have a poor
response can look at pregnancy success rates and decide
whether it is worthwhile to go through with their cycle or
even go through IVF again. Unfortunately, the information
becomes available after the cycle has been undertaken. Last,
our findings suggest that pregnancy rates should be reported
in a different manner. Ovarian reserve and ovarian response
should be included to provide a more accurate picture of IVF
outcome.
In summary, many factors are used to predict IVF success.
Maternal age, although viewed as the main predictor of
outcome, can be modified by ovarian reserve and ovarian
response. We illustrated that ovarian response alone could
predict a doubling of clinical pregnancy rate in an ageindependent fashion for most age categories. These findings
give a more accurate picture of expected clinical pregnancy
rates for patients who are undergoing IVF.
Vol. 83, No. 1, January 2005
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