RBMOnline - Vol 11. No 4. 2005 452–454 Reproductive BioMedicine Online; www.rbmonline.com/Article/1927 on web 10 August 2005
Luca Dal Prato was born in 1961. He studied medicine at the University of Bologna, Italy,
and became MD in 1986. He completed his Obstetrics and Gynecology residency in the
Department of Obstetrics and Gynecology of the University of Bologna (under Professor
Carlo Flamigni) in 1990. From 1990 to 1996 he worked as a post-graduate fellow at the
Reproductive Medicine Unit of the University of Bologna. Since 1996 he has been working
as physician at Tecnobios Procreazione, Centre for Reproductive Health in Bologna. He
has carried out investigations in the use of GnRH agonists and gonadotrophins for ovarian
stimulation in assisted reproduction treatments.
Dr Luca Dal Prato
Luca Dal Prato1,3, Andrea Borini1, Monica Cattoli1, Maria Serena Preti1, Lucia Serrao1, Carlo Flamigni2
1Tecnobios Procreazione, Centre for Reproductive Health, Via Dante 15, I-40125 Bologna, Italy;
3Correspondence: Fax: +39 051 2867512; e-mail: email@example.com
, Carlo Flamigni, Carlo Flamigni
University of Bologna,
Pregnancies after IVF have been reported in women aged ≥44 years, but nobody older than 45 years at oocyte retrieval
delivered. We report a case of birth of a healthy child after IVF in a 46-year-old infertile woman. Ovarian stimulation was
performed with clomiphene citrate, 150 mg daily for 5 days. Three oocytes were retrieved and one embryo was replaced. The
patient delivered a healthy male infant after Caesarean section at 39 weeks. A successful pregnancy after IVF with homologous
oocytes can be achieved in women older than 45 years. At this age IVF is not a cost-effective treatment compared with oocyte
donation, but it may be offered in countries in which gamete donation is forbidden.
Keywords: advanced maternal age, delivery, IVF outcome, live birth
It is well known that a woman’s fertility progressively declines
with advancing age. This decrease is slow until the end of the
fourth decade, then accelerates reaching almost zero between 45
and 50 years of age (Menken et al., 1986). A number of factors
are involved in this phenomenon, including a progressive
depletion of the ovarian follicular reserve (Richardson et al.,
1987), poorer oocyte quality (Navot et al 1987), poorer oocyte quality (Navot et al1987), poorer oocyte quality (Navot
age (Borini et al., 1995).
., 1991) and uterine
Since more couples are now delaying the beginning of child
bearing, an increasing number of women apply to fertility centres
in order to achieve a pregnancy in the last years of their fertile
age. According to a recent report (Elizur et al age. According to a recent report (Elizur et al age. According to a recent report (Elizur
of women attending IVF clinics are aged >40 years. However,
as with natural fertility, assisted reproductive technology gives
markedly worse results when the woman is aged over 40 years
(Piette et al., 1990; Elizur et al ., 1990; Elizur et al ., 1990; Elizur ., 2005). The response to ovarian
stimulation steadily deteriorates with advancing age, requiring
larger amounts of gonadotrophins, and the cancellation rate is
higher in women over the age of 40 years (Lass et al., 1998).
The fertilization rate has been shown to be similar to that of
younger women, despite the lower number of oocytes collected
(Romeu et al., 1987), but pregnancy rate is signifi cantly lower.
., 2005) 12.3%
At the same time the miscarriage rate progressively increases
(Lass et al., 1998).
The case reported here is the birth of a healthy child after IVF
in a woman who was 46 years old when she underwent oocyte
When she approached our centre, the patient was a nulliparous
46-year-old woman with secondary infertility. She had two
spontaneous pregnancies when she was 36 and 41 years old;
both ended with a miscarriage. Thereafter she could not become
The menstrual cycles were regular. A hysteroscopy performed
before starting any assisted reproductive technology procedure
was normal. Early follicular phase FSH concentration in the
cycle preceding the treatment was 11 IU/ml. The semen analysis
in the husband showed normozoospermia with moderate
The patient underwent ovarian stimulation with human
menopausal gonadotrophin (HMG, Menogon; Ferring, Milan,
Italy), 450 IU daily. An ultrasound performed after 5 days
Live birth after IVF in a 46-year-old woman
showed no follicular development and serum 17β-oestradiol
concentration was 17 pg/ml. HMG daily dose was increased up
to 750 IU for three additional days, then the cycle was cancelled
because no ovarian response was achieved.
After two menstrual periods, a second treatment was
performed with clomiphene citrate (Serofene; Serono, Rome,
Italy), 150 mg daily from day 2 to day 6 of the cycle. On
day 14 the patient had one follicle of 18 mm in diameter, one
of 14 mm and three of 10 mm, and a trilaminar endometrial
stripe measuring 9 mm. Final maturation was then triggered
with human chorionic gonadotrophin (Profasi HP; Serono),
5000 IU. Three oocytes were retrieved transvaginally under
ultrasound guidance 36 h later, and were inseminated by
conventional IVF. One oocyte fertilized and one 2-cell embryo
was replaced in the uterine cavity via a transcervical route two
days after oocyte retrieval. Luteal phase was sustained with
natural progesterone in oil (Prontogest, AMSA, Rome, Italy),
50 mg i.m. daily from day 1 after oocyte retrieval.
Fifteen days after embryo transfer, blood β-human chorionic
gonadotrophin (β-HCG) test was positive. Ultrasound scan
performed 4 weeks after embryo transfer confi rmed the
presence of one intrauterine gestational sac with cardiac
The patient underwent elective Caesarean section at 39 weeks
and delivered a healthy male infant weighing 3380 g.
As far as is known, this is the fi rst report in the literature of a
pregnancy successfully ended with the delivery of a healthy
child after IVF in a woman older than 45 years.
Women older than 45 years can have successful spontaneous
pregnancies, even if this is a very rare event in the general
population. A study on orthodox Jewish sects that are
proscribed from using contraceptives (Laufer et al., 2004)
showed that natural pregnancies and deliveries after 45 years
constitute only 0.2% of total deliveries, and that more than
80% of them occurred in grand-multiparas.
Some studies have reported on pregnancies achieved after
IVF (Lass et al., 1998; Ron-El et al., 2000; Jansen, 2003) or
gamete intra-Fallopian transfer (GIFT) (Bopp et al., 1995) in
women aged ≥44 years, but none of those who were older than
45 years when they underwent oocyte retrieval, delivered.
The analysis of 431 cycles of IVF or intracytoplasmic sperm
injection (ICSI) in women over the age of 41 years (Ron-El et
al., 2000) reported a mean delivery rate per retrieval of 2–7%
in women aged 41–43 years, but there were no deliveries in
women aged more than 43 years and no pregnancies at the age
of 45 years.
Actually, it has been reported that not only is pregnancy rate
inversely correlated with maternal age, but also that older
patients have a higher risk for miscarriage (Lass et al., 1998).
The major cause of higher pregnancy losses seems to be
chromosomal aneuploidy (Spandorfer et al., 2004), therefore
there is no therapeutic tool able to improve live birth rate in
Some studies have suggested that transferring more embryos
into the uterus might increase the pregnancy rate in older
women (Widra et al., 1996; Adonakis et al., 1997). However,
in clinical practice, the availability of more than three embryos
for transfer is not that frequent in women aged over 42–43
years. In the present case three oocytes were retrieved, but only
one embryo was available for transfer. Furthermore, in the
authors’ experience, it is very infrequent to have more than two
embryos available for transfer in women aged over 44 years.
A study performed 10 years ago compared the results of IVF
and of oocyte donation in women older than 44 years (Yaron et
al., 1995). It reported no clinical pregnancies in 52 IVF cycles,
while a 17% clinical pregnancy rate per transfer was achieved
in 22 cycles of egg donation (Yaron et al., 1995). These results
suggest that oocyte donation from young donors is the best
option for aged infertile woman, confi rming previous reports
(Meldrum, 1993; Sauer et al., 1994). More recently (Antinori
et al., 2003), a 28% delivery rate has been reported in 1288
cycles of oocyte donation in women aged 45–63 years.
The patient reported on here underwent oocyte retrieval when
she was aged 46 years, and delivered a healthy baby when she
was 47 years. This demonstrates that a successful pregnancy
after IVF with homologous oocytes can be achieved in women
≥45 years of age, but it should be considered an extraordinary
event. The authors are aware that IVF is not a cost-effective
procedure at this age, but, since oocyte donation is no longer
available in Italy, because the new law does not allow gamete
donation, IVF with their own oocytes is the only chance of
bearing a child that we can offer to older women with at least a
partially preserved ovarian reserve.
This patient in this report had no ovarian response to
gonadotrophin stimulation, but three viable oocytes could be
retrieved after clomiphene citrate treatment. Clomiphene, alone
or with gonadotrophins, has been diffusely used in the past for
IVF and demonstrated effectiveness, cheapness, high patient
compliance and reduced need for monitoring, notwithstanding
an anti-oestrogenic effect on the endometrium (Out and
Coelingh Bennink, 1998) and a possible risk of ovarian cancer
after extensive use for more than 12 treatment cycles (Rossing
et al., 1994). With the introduction of gonadotrophin-releasing
hormone (GnRH) agonists and later of GnRH antagonists
together with new gonadotrophin formulations, other protocols
have been proven to be much more effective in terms of
oocytes retrieved and clinical pregnancy rates (Smitz et al.,
1992). However, this advantage may not be signifi cant in those
women with a previous poor response to gonadotrophins. It
was suggested (Awonuga and Nabi, 1997) that for such poor
responders, three attempts of IVF in a clomiphene citrate cycle
may offer a viable therapeutic alternative before reverting to
more stressful, expensive, and time-consuming treatment.
In conclusion, a successful pregnancy after IVF with
homologous oocytes can be achieved in women ≥45 years
of age, but it is a very rare event. This is not a cost-effective
treatment in such an age group compared with oocyte donation.
However, it may be offered, after having informed the couple
of the low odds of success, in countries like Italy, in which the
law does not allow gamete donation. In such cases clomiphene
treatment can be proposed as a more cost-effective protocol
than treatment with gonadotrophins.
Case report - Live birth after IVF at 46 years - L Dal Prato et al.
Case report - Live birth after IVF at 46 years - L Dal Prato et al. Download full-text
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Received 24 June 2006; refereed 28 June 2005; accepted 11 July 2005.