Human Reproduction, Vol.29, No.9 pp. 1925 –1930, 2014
Advanced Access publication on June 20, 2014 doi:10.1093/humrep/deu137
ORIGINAL ARTICLE Infertility
Reproductive choices and outcomes
after freezing oocytes for medical
reasons: a follow-up study
T. Dahhan*, E.A.F. Dancet, D.V. Miedema, F. van der Veen
and M. Goddijn
Centre for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Centre, Meibergdreef 9, 1105, Amsterdam,
AZ, The Netherlands
*Correspondence address. Centre for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Centre,
Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands. Tel: +31-20-5663453; E-mail: [email protected]
Submitted on February 21, 2014; resubmitted on April 22, 2014; accepted on May 14, 2014
study question: What reproductive choices do women make after they have cryopreserved oocytes for medical reasons?
summary answer: Women who had cryopreserved oocytes for medical reasons and tried to become pregnant, either attempted natural
conception or resorted to assisted reproduction with fresh oocytes.
what is known already: Women confronted with a risk of premature ovarian insufficiency, due to gonadotoxic therapy, ovarian
surgery or genetic predisposition, have an indication to cryopreserve oocytes. Many of these women will retain ovarian function, thus will
retain the possibility of natural conception. The added value of cryopreserved oocytes to reproductive outcomes is unknown as there is a lack
of follow-up of women who have cryopreserved oocytes for medical reasons.
study design, size and duration: This follow-up study included a cohort of 85 women who cryopreserved their oocytes for
medical reasons between 2009 and 2012.
participants/materials, setting and methods: Medical data from women who cryopreserved their oocytes at the
Centre for Reproductive Medicine in the Academic Medical Centre in Amsterdam were extracted and self-report questionnaires were disseminated. The collected data considered demographics, outcomes of ovarian stimulation, fertility-threatening treatments, menstrual cycle changes,
pregnancy attempts and outcomes and intended plans for the cryopreserved oocytes.
main results and the role of chance: A total of 68 women, followed up for an average 25.3 months, returned the questionnaire (response rate: 80%). None of the women had used her cryopreserved oocytes although 16 women had tried to conceive. Of these women,
eight were trying to conceive naturally, five had conceived naturally within 2 months and three had conceived with assisted reproduction not requiring cryopreserved oocytes (two women with conventional IVF because of tubal pathology and endometriosis and one woman with IUI
because of polycystic ovary syndrome). Three out of the eight pregnancies had resulted in live births, two resulted in miscarriages and three
were ongoing. Most women (71%) intended to conceive with their cryopreserved oocytes as a last resource option.
limitations, reasons for caution: Transferability of our findings is challenged by the small sample but positively affected by our
high response rate. As the time span between cryopreservation of oocytes and follow-up was short, follow-up of the cohort should be repeated in
2 years.
wider implications of the findings: After a mean follow-up of 2 years, none of the women with a medical reason to cryopreserve oocytes had used her oocytes. Women who were trying to conceive during follow-up were doing so without using their stored oocytes. It is
unclear whether starting assisted reproduction while having cryopreserved oocytes is the most appropriate clinical decision. Our findings emphasize the relevance of taking the chances of natural conception into account in counselling women about cryopreservation of oocytes.
study funding/competing interest(s): This study was not externally funded. There are no conflicts of interest to declare.
Key words: oocyte cryopreservation / fertility preservation / reproductive choices / gonadotoxic treatments / primary ovarian insufficiency
& The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
For Permissions, please email: [email protected]
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Introduction
Women confronted with a risk of premature ovarian insufficiency (POI)
due to gonadotoxic therapy, ovarian surgery or genetic predisposition
have a medical reason to undergo fertility preservation (FP) (Bedoschi
and Oktay, 2013).
Cryopreservation of embryos has long been the only option to preserve fertility, but it is slowly being overtaken by cryopreservation of
oocytes since this technique allows for reproductive autonomy and
has similar pregnancy rates (Kuwayama et al., 2005; Grifo and Noyes,
2010; Rienzi et al., 2010). The efficacy of this technique and the reassuring
data on the health of babies conceived with cryopreserved oocytes
(Noyes et al., 2009) led to the removal of the experimental connotation
of cryopreservation of oocytes by the American Society of Reproductive
Medicine (Loren et al., 2013). Nevertheless, the timely need to evaluate
the added value of newly introduced techniques by means of follow-up
has been acknowledged (Harper et al., 2012).
The likeliness of chemotherapy to induce POI depends on the dose,
agent, number of cycles of chemotherapy and age of the patient (Bines
et al., 1996; Meirow, 1999; Burstein and Winer, 2000; Meirow et al.,
2010). A recent follow-up study on fertility in women who cryopreserved ovarian tissue because of planned gonadotoxic chemotherapy,
revealed that the majority retained ovarian function with an overall risk
of POI of 22% after a mean follow-up of 58 months (Schmidt et al.,
2013). Pregnancy rates of 65% are described in childhood cancer survivors (Nielsen et al., 2013), even when trying to conceive naturally for
longer than 1 year (Barton et al., 2013).
Data on the risks of POI in women with Mosaic Turner Syndrome are
based on a limited number of studies indicating loss of ovarian reserve in
women with karyotypes associated with poor fertility prognosis (such as
Xq deletions and 45XO) but natural conceptions rates are rarely mentioned in literature (Tarani et al., 1998; Sybert, 2002; Purushothaman
et al., 2010). Women with a mother with a history of POI are at risk
for developing POI themselves, but natural conception rates are
unknown (Bentzen et al., 2013).
Considering the increased awareness about FP, a result of the tremendous efforts of organizations like the American Society for Clinical
Oncology, Fertile Hope, the International Society for Fertility Preservation, the Oncofertility Consortium and local initiatives (i.e. the DutchNetwork for FP), it is likely that we will enter an era in which many
women have anticipated their risk of POI and cryopreserved their
oocytes. Since many of these women will retain ovarian function,
chances of natural conception will be present while cryopreserved
oocytes are stored. The added value of cryopreserved oocytes to reproductive outcomes is unknown in these women, as there is a lack of a comprehensive follow-up of women who have cryopreserved oocytes for
medical reasons and insight into women’s intentions for their cryopreserved oocytes is lacking. This study therefore aimed to examine the reproductive choices and outcomes of women who have cryopreserved
their oocytes for medical reasons.
Methods
Ethical approval
This follow-up study was conducted in August 2013. The Institutional Review
Board of the Academic Medical Centre (AMC) Amsterdam (project no
Dahhan et al.
W13_091), stated that the study was not subject to the Dutch ‘Medical
Research Involving Human Subjects Act’, meaning that no further approval
was required.
Study population
A cohort of 85 women, who had cryopreserved oocytes between January
2009 and December 2012, because of medical reasons, at the Centre for
Reproductive Medicine of the AMC in Amsterdam was eligible for follow-up.
Data collection
Medical data on the indication for cryopreservation of oocytes, ovarian
stimulation and the results of oocyte cryopreservation were extracted
from medical files.
A paper– pencil questionnaire was developed and consecutively pilot
tested. The questionnaire finally covered five topics: established medical
diagnosis and fertility-threatening treatment received, menstrual cycle
changes and use of contraception, attempts to conceive and intended plan
for (residual) cryopreserved oocytes. All 14 questions had a multiple
choice response scale but for each, the possibility to add explanations was
provided (see Supplementary data, File 1).
Up to date contact information (i.e. postal addresses) of the entire cohort
of women was retrieved from the central hospital register of the AMC.
The questionnaire was coded and sent by mail in August 2013 accompanied by an invitation and information letter and possibility to declare no interest
in participation. Three weeks later, non-responders were reminded by mail
and again by telephone after another 3 weeks.
Data-analysis
Data were entered and analyzed using SPSS statistics 20. Descriptive statistics
were computed to describe demographics, indications for oocyte cryopreservation, reproduction after oocyte cryopreservation, menstrual cycle
changes and intended use of (residual) cryopreserved oocytes.
Results
Respondents
The flowchart of the recruitment of the study cohort is shown in Fig. 1. A
total of 85 questionnaires were sent, and 68 women completed the questionnaire and returned it by post (80%). Demographics of these women
are shown in Table I. The mean age at time of oocyte retrieval for cryopreservation was 30.2 years (range 18 –40 years) and only two women
(3%) had children at the time of cryopreservation of oocytes. The majority (75%) of the women were highly educated. Women went through one
(n ¼ 30; 44%), two (n ¼ 23; 34%), three (n ¼ 13; 19%) or four consecutive cycles (n ¼ 2; 3%). Three women (5%) cryopreserved oocytes in
2009, 13 women (19%) in 2010, 21 women (31%) in 2011 and 21
women (31%) in 2012. The mean time to follow-up was 25.3 months
(range 9– 50 months).
Indications for cryopreservation of oocytes
At the time of follow-up, 35 women (51%) reported having undergone
therapy which contained cyclophosphamide. Other fertility-threatening
treatments were chemotherapy consisting of doxorubicin, bleomycin, vinblastine and darcarbacine (ABVD) (n ¼ 4), chemotherapeutic preparation
for bone-marrow transplantation (n ¼ 1), endocrine therapy only (n ¼ 1),
methotrexate (n ¼ 1) and bilateral salpingo-oophorectomy (BSO)
because of a BRCA1 gene mutation (n ¼ 1).
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Choices and outcomes after oocyte cryopreservation
Figure 1 Flowchart study cohort of women who cryopreserved oocytes for medical reasons from 2009 to 2012.
Table I Demographics of 68 women who cryopreserved
oocytes for medical reasons from 2009 to 2012.
Demographic characteristic
Mean (range)
N (%)
........................................................................................
Mean age at time of oocyte retrieval
30.2 years (18 –40)
Previous children
2/65 (3)
Higher professional school or
university
41/55 (75)
Dutch origin
BMI (kg/m2)
52/55 (95)
23.3 (17.3– 33.7)
Non-smokers
47/60 (78)
Regular cycle
29/38 (76)
Women undergoing one cycle
30 (44)
Women undergoing two cycles
23 (34)
Women undergoing three cycles
13 (19)
Women undergoing four cycles
2 (3)
Mean number of cryopreserved
oocytes per woman
16.5 (1–36)
Mean number of cycles per woman
1.8 (1– 4)
Mean time of follow-up
25.3 months (9– 50)
BMI, body mass index.
Out of the 34 women with breast cancer, 23 women (68%) were
undergoing additional endocrine therapy because of hormone-sensitive
breast cancer at time of follow-up, which made conception ill advised
(11 women were using tamoxifen; 9 women were using tamoxifen and
GnRH analogues, 2 women were using GnRH analogues and 1 woman
did not remember the name of her endocrine breast cancer treatment).
One of these women however was trying to conceive after a wash out
period to clear the tamoxifen.
Reproduction after cryopreserving oocytes
Out of the 68 women, 16 women had tried to conceive after cryopreservation of oocytes; eight women were trying to conceive naturally at time
of follow-up (of whom one woman was using donor insemination) and
eight women had already became pregnant without using their cryopreserved oocytes. Of the eight women who had already became pregnant,
five conceived naturally and all within the first 2 months of trying. These
five pregnancies resulted in one live birth, two miscarriages and two
ongoing pregnancies (at gestational ages of respectively 8.5 and 9
weeks). The three other women became pregnant with assisted reproductive techniques (two using conventional IVF and one using IUI). The
reasons for starting conventional IVF after cryopreservation of oocytes
were bilateral tubal pathology in one woman who had undergone unilateral ovariectomy and endometriosis in the other woman. Both women
had live births after conventional IVF. IUI with ovarian stimulation was
performed in a woman with a family history of POI and polycystic
ovarian syndrome, which became apparent after cryopreservation of
oocytes. This woman reported a pregnancy at 9 weeks gestational age.
Of the remaining 52 women who were not trying to conceive, 22 were
using endocrine therapy for breast cancer which made conception illadvised, two women had a contraindication for pregnancy due to unstable auto-immune disease and 14 women did not have a male
partner. In total, 14 women (21%) were not trying to conceive despite
having a male partner and being medically allowed a pregnancy.
Menstrual cycle changes
Questions about changes in menstrual cycle could be answered by
28 women as they did not use any medication that could mask their
menstrual cycle (i.e. oral contraception). All 28 women retained
their menstrual cycle at time of follow-up. One woman with Mosaic
Turner syndrome reported having noticed a change from a regular
cycle (28 –30 days) to an irregular cycle of 30 –35 days after a follow-up
of 15 months.
Intended use of cryopreserved oocytes
The majority of the responding women (n ¼ 48; 71%) reported that they
would use their cryopreserved oocytes if they had difficulties conceiving
naturally. Additionally, 19 women (28%) had no specific plan with their
cryopreserved oocytes and one woman wanted to donate her cryopreserved oocytes to research. When asked their intentions in case of
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residual cryopreserved oocytes, some women reported not to have a
plan in mind (35%), whereas others planned to donate their residual
oocytes in the future to research (26%), either to research or other
women (13%), or only to other women (13%), whereas others would
wish to destroy their residual cryopreserved oocytes (10%) or did not
answer this question (3%).
Discussion
Cryopreservation of oocytes is becoming mainstream for women opting
for FP because this technique does not require a male partner and is no
longer considered experimental (Loren et al., 2013). This follow-up study
found that after a mean follow-up of 25.3 months, women who had cryopreserved oocytes for medical reasons and tried to become pregnant,
had attempted natural conception or resorted to assisted reproduction
techniques with fresh oocytes for various reasons. So far, none of the
cryopreserved oocytes had been used. Half of the women attempting
to conceive became pregnant, mostly by natural conception. This is
the first follow-up study in women who have cryopreserved oocytes
for medical reasons, to report all reproductive outcomes, including outcomes resulting from the choice not to use cryopreserved oocytes.
None of the women in our study reported clinical symptoms indicating
an onset of menopause (defined as an absence of menstrual cycle for
longer than one year without using hormonal contraception or endocrine therapy for breast cancer). It was impossible to detect symptoms
of impaired ovarian function for the total study cohort, since most
women in this study used hormonal therapy masking their menstrual
cycle.
Our study found that 50% of the women cryopreserving oocytes for
medical reasons did so because of breast cancer. The relatively large proportion of women with breast cancer opting for FP in our study was also
found in a large retrospective cohort of 475 oncological patients, in which
the majority of women cryopreserving oocytes were diagnosed with
breast cancer (Garcia-Velasco et al., 2013). Breast cancer is the most
common malignancy of women of reproductive age and its management
usually includes gonadotoxic chemotherapy regimens with cyclophosphamide. In case of hormone-sensitive breast cancer, prolonged endocrine treatment with tamoxifen or aromatase-inhibitors for 5 years is
recommended after chemotherapy (Davies et al., 2011). Women are
frequently advised by their oncologists to postpone motherhood
during therapy with tamoxifen because of possible teratogenicity
(Barthelmes and Gateley, 2004; Braems et al., 2011). In case women
do opt for a pregnancy during tamoxifen use, such as one woman in
our cohort, a wash out period of at least 2 months is advised (Braems
et al., 2011). Moreover, as was the case in one woman of our cohort,
women who carry a BRCA1/2 gene mutation may have to prophylactically undergo BSO before they have had a chance to conceive. Therefore,
the fertility of women with breast cancer is at an even greater threat.
As reported in this study, women who have cryopreserved oocytes in
the past may not rely on their cryopreserved oocytes in the future due to
maintenance of natural chances of conception. This is in accordance with
data from women who had cryopreserved oocytes for age-related
decline of fertility, where ,1% of women who achieved a pregnancy
after cryopreservation of oocytes made use of her cryopreserved
oocytes (Hodes-Wertz et al., 2013). Additionally, one study reported
that in 143 women who cryopreserved ovarian tissue because of gonadotoxic treatment, 46 women became pregnant after treatment
Dahhan et al.
(32%), of whom 41 women (89%) conceived naturally (Schmidt et al.,
2013). This is a higher proportion than that found in our study. The difference might be explained by a longer follow-up time in this study compared with our study (mean of 58 versus 25 months) and the relatively
high number of women with breast cancer in our study, who were still
undergoing additional endocrine therapy at time of follow-up, disabling
them from conceiving. It is difficult to define the appropriate timespan
after which to start follow-up. Our relatively short time to follow-up
(mean of 25.3 months) results in the need to repeat this study in 2
years. On the other hand, the need for timely critical reflection on
newly introduced techniques (Harper et al., 2012) and the finding in
our study, that half of the women who were already trying to conceive
did not need to rely on their cryopreserved oocytes, demonstrates the
timeliness of our study.
Of the 52 women who were not trying to conceive, only 14 women
had a male partner and had no medical contraindication to pregnancy.
Although this study did not thoroughly question motivations for not
conceiving, fears about pregnancy-related risks after surviving cancer
may contribute to postponing motherhood (Schover, 2005; Gonçalves
et al., 2013).
Transferability of our findings is challenged by the small sample size but
positively influenced by our high response rate. Another limitation of our
study was that assessment of ovarian function (i.e. blood sampling or
transvaginal ultrasound) was not included in the study design. Therefore,
the decisions of women (and their advising physicians) on when and how
to start trying to conceive was not influenced by knowledge about
ovarian reserve. It is likely that having undergone fertility-threatening
treatment influenced decisions on the timing of attempting conception.
In our study population, 75% of women were highly educated (higher
professional school or university), whereas only 28% of the general
Dutch population is highly educated. The overrepresentation of highly
educated women opting for cryopreservation of oocytes is also found
in other cohorts of women cryopreserving oocytes (Stoop et al., 2011;
Hodes-Wertz et al., 2013). A possible explanation is that highly educated
women are prone to delay motherhood (Heck et al., 1997) and may be
more assertive in asking about possible fertility related risks of medical
treatments and subsequent options to preserve fertility. Data available
to gain insight into the pregnancy chances for this study population are
based on comparisons of pregnancy rates of fresh oocytes by conventional IVF with cryopreserved and thawed oocytes, showing no superiority of fresh oocytes over cryopreserved oocytes (Cobo et al., 2008;
Rienzi et al., 2012). Our study showed that two women with a pregnancy
wish after cryopreservation of oocytes relied on fresh conventional IVF. It
is debatable whether conventional IVF/ICSI indications justify the use of
conventional IVF in women who have already undergone IVF for cryopreservation of oocytes, which in this respect can be regarded as an
‘unfinished IVF’ treatment. From a pragmatic and cost-effectiveness
point of view, one might opt for using cryopreserved oocytes first
before initiating a new fresh IVF cycle. On the other hand, from the perspective of age-related fertility decline, one might choose to undergo
conventional fresh IVF first before using the cryopreserved oocytes.
This implies that the rationale for cryopreserving oocytes has then
changed from a medical reason into a non-medical reason, which may
be an ethical dilemma.
In conclusion, this study found that after a mean follow-up of 2 years,
none of the women with a medical reason to cryopreserve oocytes had
used any of these oocytes, and all women attempting to conceive after
Choices and outcomes after oocyte cryopreservation
cryopreservation of oocytes were doing so without the use of the stored
oocytes. There is a need to develop tailored prognostic and prediction
models to personalize chances of obtaining a pregnancy with or
without use cryopreserved oocytes. It may be too soon to predict
these chances because cryopreservation of oocytes has been introduced
only recently and rates at which these occytes are used are inherently
low. The results of this study emphasize the importance of taking the
chances of obtaining a pregnancy without use of cryopreserved
oocytes (e.g. by natural conception) into account when counselling
women on live birth rates after cryopreserving oocytes and when designing new studies that evaluate pregnancy rates in the setting of oocyte
cryopreservation.
Supplementary data
Supplementary data are available at http://humrep.oxfordjournals.org/.
Acknowledgements
We thank all women participating in this study for their time and efforts to
answer the questionnaire. We thank Annemieke de Melker and Alexandre Soufan for their assistance in data collection. We especially
thank the centre for reproductive medicine in the AMC for facilitating
the procedures of this study.
Authors’ roles
T.D., E.D., M.G. and F.V. designed the study. D.M. collected data from
the medical files and questionnaires. T.D. drafted the manuscript. All
authors revised and corrected the drafts and approved the final
version of the manuscript.
Funding
This study was not externally funded.
Conflict of interest
None declared.
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