Spontaneous conception in a 50-year old woman after giving up in-vitro-fertilization (IVF) treatments: Involvement of the psychological relief in successful pregnancy

Abstract

A healthy woman, married at age 45, hoped to have their child without delay. She and her husband subsequently decided to pursue in-vitro-fertilization and embryo transfer (IVF-ET). In the succeeding year, ET was performed twice from four oocyte retrieval attempts, which represented six ovarian stimulation cycles. Pregnancy was not achieved. Because of her poor responses to ovarian stimulation, inferior oocyte grading and prohibition of donor oocyte usage in Japan, the couple decided to discontinue further IVF treatment at age 48 years, 10 months. One and one-half years later, at age 50 years, 3 months she presented to our clinic eight weeks pregnant. At term she delivered vaginally a 2740 g healthy infant at 38 weeks gestation; Apgar scores were 9 and 10. During her pregnancy, she willingly participated in our questionnaire designed to provide information about her psychological well-being during the past three years. During the time spanning her treatment for infertility, anxiety, depression, irritability, fatigue and grief were revealed to coexist with her high hopes of having a child. After termination of infertility treatments these adverse psychological findings were markedly lessened and her vigour was restored. Stopping infertility treatment might be a viable alternative for achieving pregnancy in similarly psychologically-challenged infertile women.

Full text

INTRODUCTION
Advancing female age is a well-documented
problem in achieving a successful pregnancy
[1, 2]. By using donated oocy tes, women
have become pregnant in thei r late 50 ’s
and older [3, 4]. Thus, it appears that the
age-related decline in fertility is due primar-
ily to oocyte aging [5, 6]. In Japan, however,
oocyte donation is prohibited. Therefore,
infertility treatment ends with menopause
or by anovulation, the latter including pre-
mature ovarian failure. When this occurs,
most couples discontinue further treatments,
however, some couples chose to go to other
countries to seek donor oocytes and undergo
additional IVF attempts. As a consequence,
infertile Japanese women view aging with
apprehension, especia lly wit h regard to
their oocyte quality and/or their potential to
remain eligible for continuation of infertil-
ity treatments. Therefore, most Japanese
Gynecologist believe and advise that women
over 40 years old who want to have their
children should choose IVF-ET in earlier
convenience. Once IVF-ET was performed,
however, it is difficult to cease I VF- E T,
because we don’t have other option to give
such older women.
To our knowledge, the oldest spontaneous
conception occurred in a 60-year old woman
in 1998, which was reported in a UK news-
Spontaneous Conception in a 50-year Old Woman
after Giving up In-Vitro-Fertilization (IVF) Treatments:
Involvement of the Psychological Relief in Successful Pregnancy
Hidehiko MATSUBAYASHI, Katsuhiko IWASAKI, Takashi HOSAKA
＊,
Yoko SUGIYAMA
＊, Takahiro SUZUKI, Shun-ichiro IZUMI, and Tsunehisa MAKINO
Department of Obstetrics and Gynecology, Center for Growth and Reproductive Medicine and
*Department of Psychiatry and Behavioral Science, Center for Internal Medicine,
Tokai University School of Medicine
(Received November 8, 2002; Accepted January 7, 2003)
A healthy woman, married at age 45, hoped to have their child without delay. She and her
husband subsequently decided to pursue in-vitro-fertilization and embryo transfer (IVF-ET).
In the succeeding year, ET was performed twice from four oocyte retrieval attempts, which
represented six ovarian stimulation cycles. Pregnancy was not achieved. Because of her poor
responses to ovarian stimulation, inferior oocyte grading and prohibition of donor oocyte
usage in Japan, the couple decided to discontinue further IVF treatment at age 48 years, 10
month s. One and one-half years later, at age 50 years, 3 months she presented to our clinic
eight weeks pregnant. At term she delivered vaginally a 2740 g healthy infant at 38 weeks ges-
tation; Apgar scores were 9 and 10. During her pregnancy, she willingly participated in our
questionnaire designed to provide information about her psychological well-being during the
past three years. During the time spanning her treatment for infertility, anxiety, depression,
irritability, fatigue and grief were revealed to coexist with her high hopes of having a child.
After termination of infertility treatments these adverse psychological findings were mark-
edly lessened and her vigour was restored. Stopping infertility treatment might be a viable
alternative for achieving pregnancy in similarly psychologically-challenged infertile women.
Key words : aging, distress, IVF-ET, infertility, Japan.
Tokai J Exp Clin Med., Vol. 28, No. 1, pp. 9-15, 2003
Hidehiko MATSUBAYASHI , Department of Obstetrics and Gynecology, Center for Growth and Reproductive Medicine, Tokai
University School of Medicine, Bohseidai, I sehara, Kanagawa 259-1193, Japan Fax: 81+463 -91-4343 ; e-mail: hide-m @is.icc.u-
tokai.ac.jp

10 ―H. MATSUBAYASHI et al.
paper. We now report a spontaneous concep-
tion in a 50-year old woman 1.5 years after
withdrawing from IVF treatment because of
inferior oocyte grading and poor oocyte re-
trieval. We believe that our patient represents
the eldest example on record of a spontane-
ous conception and delivery after cessation
of IV F treatment. This case suggests that
only continuation of IVF treatment may not
be appropriate for such older women and
that quitting IVF treatment does not always
mean giving up being pregnant, because
psychological factor cannot be excluded.
CASE REPORT
A healthy, nulligravid woman married
at age 45 experienced two early pregnancy
losses at ages 46 and 47. The first loss was at
eight weeks (positive fetal heart tones) and
the second loss was at seven weeks (blighted
ovum) of gestation. After her second mis-
carriage, at 47 years 3 months of age, she
presented to our infertility clinic. She and
her husband hoped to have their child with-
out delay. Her husband’s semen analyses
showed slightly asthenozospermia (40-45 %)
but total motile sperm was normal (20-28
×106). She opted to circumvent our routine
work-up for infertility except for hormonal
tests because she had had two documented
pregnancies, and, in view of her age, she did
not want to undergo the usual tests for re-
current pregnancy loss. Her menstrual cycle
historically had been 30 days, but it was
irregular during the past 2 years (20-60 days
cycle). Ultrasound examination revealed her
uterus and both ovaries to be unremarkable.
Her basal follicle-stimulating hormone (FSH)
level was normal (3.4 IU/L), and she did not
have hyperprolactinemia or a luteal phase
defect. She didn’t have psychiatric disorders.
During first 4 months, she was advised to
have coitus at the day of ovulation monitored
by ultrasound, but not pregnant. In suc-
ceeding 3 months, intrauterine insemination
with her husband’s sperm was performed
in view of asthenozospermia, but failed to
conceive. She and her husband did request
IVF-ET. Their rationale for this choice was
that IVF-ET procedure had the highest preg-
nancy success rate among infertility treat-
ments, and that the residual oocytes might
not be much in her age. A clomiphene-
citrate-challenge test was performed that
showed a good response for FSH (3.4 IU/L
to 24.7 IU/L). Since there was no significant
difference between clomiphene citrate plus
gonadotropins and gonadotropin-releasing
hormone (GnRH ) agonist combined with
gonadotropins for patients over 40 in our
institute, the former was selected for ovarian
stimulation. The first attempt for IVF result-
ed in no oocyte retrieval from either ovary.
In the second and third oocyte retrieval at-
tempts, embryo transfers with Veeck-graded
3 and 2 embryos respectively (only one
embryo per each cycle) were unsuccessful.
After these three consecutive attempts, she
became anovulatory. Two cycles of hormone
replacement therapy were instituted, but the
fourth and fifth oocyte recovery attempts
were abandoned as no growing follicles
were detected. Her basal FSH level was 41.6
IU/L at age 48 years, 6 months. Another two
cycles of hormone replacement therapy were
performed to obtain reduced FSH levels (8.7
IU/L). To maintain the lower levels of FSH
for the sixth retrieval attempt, a long-GnRH
agonist protocol combined with gonadotro-
pins was performed, but only one degener-
ated oocyte was retrieved. In summary, no
pregnancy was achieved after two embryo
transfers were performed as a result of four
oocyte retrieval attempts and six ovarian
stimulation cycles.
After fr ank discussions abou t fut ure
expectations regarding additional infertility
treatments, she and her husband concluded
that they should cease further IVF treatment.
Their decision was based upon the wife’s
poor response to ovarian stimulation, infe-
rior-grade oocytes and prohibition of donor
oocytes usage in Japan. At age 48 years, 10
months she and her husband stopped infer-
tility clinic visits and she quit monitoring her
basal body temperature.
One and one half years later at age 50
years, 3 months, she appeared at our clinic
to say she might be pregnant. Her menstrual
cycle was also irregular (20 -60 days cycle).
At that time, her pregnancy was eight weeks
gestation and she complained of a slight
emesis. She was afraid of a fetal anomaly
because she had taken several drugs for
a common cold. We discussed the risk of
fetal anomalies resulting from the drugs and
her additional risks due to her age. After
contemplating pregnancy termination, the
couple chose to have the baby. Between 10
and 14 weeks of gestation she was admitted

Spontaneous conception at age of 50 ―11
Fig. 1 Assessment of patient feelings by using our questionnaire with visual analog scale. 1; before
visiting our infertility clinic, 2; during infertility treatments, 3; after quitting infertility treat-
ments, 4; two months before conception, 5; surrounding conception.

12 ―H. MATSUBAYASHI et al.
to our hospital for a threatened abortion
and hyperemesis gravidarum. Her thyroid
function was normal. The couple declined
amniocentesis because they had decided to
have this baby regardless of the outcome.
After that, her pregnancy was uneventful.
She was delivered at 38 weeks gestation of a
2740 g (6 lb.) infant with Apgar scores of 9
and 10. The infant was healthy without any
abnormalities.
While pregnant, she agreed to participate
in our questionnaire with visual analogue
scales (VAS) designed to ascertain retrospec-
tive information ab out her psychological
well-being for the past three years (Appendix
I). The aim of this questionnaire is to see
changing of feeling with this period, which
is not absolute but relative. Her responses
revealed that her aspirations for having
children had continued unabated during this
period (Fig. 1). Her husband remained sup-
portive throughout this period. Feelings of
pressure were scored as consistently neutral.
Tension scores were decreased temporally
when her infertility treatments were discon-
tinued, but reappeared before she became
pregnant. Anxiety, depression, irritability, fa-
tigue and grief were markedly reduced after
stopping her infertility treatments and her
vigor was restored to normal values.
DISCUSSION
The patient in our case report decided
to give up IVF treatments because of inad-
equate responses to ovarian stimulation and
poor-quality oocytes. She subsequently con-
ceived spontaneously and we observed her
conception to coincide with her psychological
assessment of relief after quitting infertility
treatment.
Spontaneous conception subsequent to the
birth of infants conceived through IVF-ET
has been reported to approximate 20 % [7,
8]. Perhaps this 20 % might not have needed
IVF treatment in the past, or alternatively,
the successful delivery of an infant might
improve the environment for an unaided
pregnancy. Those authors speculated that the
most likely cause of spontaneous conception
in these women is the relief of stress, but
it was never documented by evaluation in
their papers [7, 8]. Other report observed
that spontaneous pregnancies occurred with
11 % per 5 years even in women who had
to perform intracytoplasmic sperm injection
(ICSI) treatment to get fertilized eggs (i.e.,
no fertilization without IC SI) [9] . We also
have noticed that some unexplained infertile
women be come pregnant spontaneously
after geographic relocations, changing or
quitting jobs, transferring to another clinic,
as well as discontinuing their infertility treat-
ments (unpublished observations). Together
these findings suggest that psychological
factors are of concern in certain infertile
patients.
The underlying reasons responsible for
th ese sponta ne ous pregnancies in these
“infertile” patients awaits closer scrutiny as
assessments of psychological well-being can-
not be made for women who have not been
tested or followed. We can’t follow women
who give up to have a child, because they
have no reason to come to infertility clinic.
Clearly, many questionnaires used for psy-
chological evaluations do not inquire about
retrospective information. To overcome this
deficit, we tried to develop an original ques-
tionnaire with VAS (Appendix I). Our ques-
tionnaire measures the intensity of mood,
which may be called as Visual Analogue
Mood Scale (VAMS). In terms of the reliabil-
ity of VAS or VAMS, test re-test reliability
and inter-rater reliability has been reported
in the same individual [10]. There were very
high correlations between the initial rating
and recall rating [10]. The accuracy of VAS
recalling for more than 2 years, however, is
still uncertain. The feature of our question-
naires is that we put a series of VAS (5 time
points) together to reduce retrospective bias,
which makes relative changes clear during
answering. It might be said that VAS should
be tested during the pilot study [10] . Since
there will be no progress in this field without
this types of questionnaires, we think that it
can provide valuable and useful information
in this situation.
This woman in our case report may not
need IVF treatment, because she had two
pregnancies before treatment. She subse-
quently, however, b ecame infertile after
coming to our clinic without conception for
20 months. She and her husband had strong
hope to perform IVF treatment to achieve
pregnancy without delay, but this choice
might be wrong. She might have her own
child earlier without infertility treatment.
It is known that infertility treatment alone
is stressful [11, 12], and failure to conceive

Spontaneous conception at age of 50 ―13
can compound this condition and lead to
depression [13] , which can be recognized
and managed [14, 15]. Although most stud-
ies have suggested that infertility or infertil-
ity treatment is a source of psychological
distress, other recent studies state that stress
may be a causal factor for infertility. Pre-
existing psychological features, for examples,
anxiety, depression, and negative emotional
states are independently related to IVF-ET
failure [16, 17]. Indeed, anxiety is correlated
with uterine contraction frequency at the
time of ET, which may induce implantation
failure [18] . Another possible explanation
is the physiological link between hormonal
changes and psychological states. Anxiety
induces hyperprolactinemia resulting in fail-
ure to conceive [19, 20]. Similarly, emotional
stress caused by either anxiety or depression
can induce changes in prolactin, cortisol and
testosterone [21, 22]. There are reports ap-
pearing that reduced scores of anxiety and/or
depression are related to successful concep-
tion [23, 24], and that counseling has been
reported to be effective in reducing anxiety
and depression [25] and result in successful
conception [26, 27].
In conclusion, infertility or infertility treat-
ment is a source of psychological distress,
but this may be a causal factor for infertility
at the same time. Most Japanese Gynecologist
believe and advise that women over 40 years
old who want to have their children should
choose IVF-ET in earlier convenience. Once
IVF-ET was performed, however, it is diffi-
cult to cease IVF-ET, because we don’t have
other option to give such older women. The
psychological release seems to be observed
in our patient after stopping infertility treat-
ment followed by successful conception.
This case suggests that simple continuation
of IVF treatment may not be appropriate to
achieve pregnant for such older women and
that quitting IVF treatment does not always
mean giving up being pregnant, because
psychological factor cannot be excluded.
Si nce studies a sses sing emo tional well-
being, infertility and fecundity have yet to
be published for women who don’t come to
infertility clinic, we hope that this case report
will stimulate others to explore this potential.
ACKNOWLEDGEMENT
This study was supported in part by a
Project Research Grant, Tokai University
School of Medicine, Japan. We thank Dr.
John A. McIntyre for reading and editing
our manuscript.
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Appendix I
Questionnaire used in our study with visual analog scales. We asked the patient to retrospec-
tively describe her feelings before, during and after infertility treatments, two months prior to
conception and surrounding conception. Questions were given in this order.
1 If you set most delighted experience at ＋100 and most sorrowful experience at −100,
express your feeling between−100 and 100 at each time point.
2 If you set most anxious experience at ＋100 and most relieved experience at −100, ex-
press your feeling between−100 and 100 at each time point.
3 If you set most pressured experience with being infertile at ＋100 and least pressured
experience at−100, express your feeling between−100 and 100 at each time point.
4 If you set most manic experience at ＋100 and most depressed experience at −100, ex-
press your feeling between−100 and 100 at each time point.
5 If you set most relaxed experience at ＋100 and most tense experience at−100, express
your feeling between−100 and 100 at each time point.
6 If you set strongest experience to hope for having children at＋100 and weakest experi-
ence at−100, express your feeling between−100 and 100 at each time point.
7 If you set having best understanding/support from your husband at ＋100 and having
worst understanding/support at −100, express your feeling between −100 and 100 at each
time point.
8 If you set most vigorous experience at ＋100 and least vigorous experience at −100, ex-
press your feeling between−100 and 100 at each time point.
−100
0 ＋100
├────────────┼────────────┤
(Sample) before visiting our infertility clinic
during infertility treatments ├────────────┼────────────┤
after quitting infertility treatments ├────────────┼────────────┤
two months before conception ├────────────┼────────────┤
surrounding conception ├────────────┼────────────┤

Spontaneous conception at age of 50 ―15
9 If you set most irritable experience at ＋100 and least irritable experience at −100, ex-
press your feeling between −100 and 100 at each time point.
10 If you set most fatiguing experience at ＋100 and least fatiguing experience at −100,
express your feeling between −100 and 100.