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IVF Outcome in Women with PCOS, PCO and Normal Ovarian Morphology
1. IVF outcome in women with PCOS, PCO and normal ovarian morphology
Alexander Swanton a
, Lisa Storey b
, Enda McVeigh b
, Tim Child b,
*
a
Royal Berkshire Hospital, Reading, RG1 5AN, UK
b
Oxford Fertility Unit, Institute of Reproductive Sciences, Oxford Business Park North, Oxford, Oxfordshire, OX4 2HW, UK
1. Introduction
Polycystic ovarian syndrome (PCOS) is the most common female
endocrine disorder, affecting 6–10% of women of childbearing age
[1]. Ultrasound evidence of polycystic ovaries (PCO) affects appro-
ximately 20–30% of the female population [2–4]. However, only a
proportion of these women are symptomatic, and although it may be
considered a normal variant, the prevalence of PCO is up to 34% of
women attending fertility clinics [5]. The large group of women with
PCO but without symptoms of PCOS (regular ovulatory cycles and no
hyperandrogenism) have been described as ovulatory PCO [6].
Women with ultrasound evidence of PCO (including anovulatory
PCOS and ovulatory PCO) appear to be at increased risk of ovarian
hyperstimulation syndrome(OHSS) whencompared towomen with
normal ovaries [7]. Studies have shown that women with ovulatory
PCO share some common metabolic characteristics with women
who havePCOS, such asincreasedinsulinresistance whencompared
to well-matched controls [8,9]. Adams et al. demonstrated that
women withovulatoryPCOhaveelevated androgenlevelsand lower
sex-hormone binding globulin levels. Patients with unexplained
infertility who have PCO have higher mid-follicular luteinising
hormone and testosterone levels compared with women with
normal ovaries [10]. Data suggest that subtle endocrine distur-
bances, similar to those that are found in PCOS, may be uncovered in
up to a third of women with ovulatory PCO [11].
There are limited data analyzing IVF outcome in women with
polycystic ovarian morphology who do not have PCOS. The aim of
this study is to assess whether women with ultrasound evidence of
polycystic ovaries alone are at significant risk of developing severe
OHSS when compared to women with PCOS and those with normal
ovarian morphology. We also wished to examine the success rates
of IVF treatment in the three patient groups.
2. Materials and methods
The IVF unit electronic database was analyzed to identify
consecutive women aged <37 years of age undergoing their first
IVF cycle. Patient details were recorded including age, menstrual
history, baseline (day 2–5) pelvic ultrasound findings, any
recorded history of hirsutism and/or acne requiring treatment,
and testosterone levels (nmol/L).
Patients were categorised into one of the three groups: those
with normal ovaries (group 1); those with PCO in the presence of
ovulatory cycles and absence of hirsutism (group 2); those with
PCOS (group 3), as determined by the Rotterdam criteria [12]. All
women in group 3 had PCO in addition to either oligo/amenorrhoea
or hyperandrogenism. Diagnosis of PCO was made by the presence
of 12 or more follicles in at least one ovary and/or ovarian volume
10 ml. Further cycles were collected until numbers were
sufficient for statistical analysis.
The main outcome measure was severe OHSS, defined as that
requiring hospitalization. We also included OHSS avoidance
techniques such as cycle cancellation and coasting. Secondary
endpoints were also analyzed including:
Number of oocytes collected.
Total dose of follicle stimulating hormone [FSH] (IU) for ovarian
stimulation.
European Journal of Obstetrics Gynecology and Reproductive Biology 149 (2010) 68–71
A R T I C L E I N F O
Article history:
Received 9 April 2009
Received in revised form 8 October 2009
Accepted 20 November 2009
Keywords:
Ovulatory polycystic ovaries
Ovarian stimulation
IVF
OHSS
PCOS
A B S T R A C T
Objective: To examine the outcome of IVF in women who have normal ovaries, ovulatory PCO or PCOS.
Study design: Analysis of a prospectively collected database in an assisted conception unit in a university
teaching hospital including 290 women 37 years of age undergoing their first IVF cycle. The main
outcome measure was severe OHSS requiring hospitalization.
Results: Severe OHSS rates were significantly higher in women with PCO (12.6%) and PCOS (15.4%)
compared to those with normal ovaries (2.7%). Coasting was used significantly more often. Live birth
rates per cycle started are similar among women with PCO (38%), PCOS (37%) and normal ovaries (40%).
Conclusion: Women with ovaries of polycystic morphology are at increased risk of developing severe
OHSS and of requiring avoidance techniques such as coasting, regardless of ovulatory status. However,
live birth rates per cycle are similar to women with normal ovaries.
ß 2009 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +44 01865 220180; fax: +44 01865 221031.
E-mail addresses: tim.child@obs-gyn.ox.ac.uk,
alex.swanton@royalberkshire.nhs.uk (T. Child).
Contents lists available at ScienceDirect
European Journal of Obstetrics Gynecology and
Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb
0301-2115/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejogrb.2009.11.017
2. Peak estradiol level [E2] (pmol/L).
Number of follicles at oocyte collection.
Number of follicles 14 mm on day 9 of stimulation.
Number of oocytes fertilized.
Normal fertilization rate (number of pronuclei embryos [2PN]).
Number of embryos frozen.
Pregnancy rate (PR).
Clinical pregnancy rate (CPR) (clinical pregnancy defined as the
presence of fetal heart activity at 6 weeks gestation).
Live birth rate (LBR).
The IVF treatment regimen using a GnRH long agonist cycle was
as follows:
Patients commenced pituitary suppression with Nafarelin
(Syneral; Pharmacia Ltd., Milton Keynes, UK) 400 mcg twice
daily intra-nasally starting on day 21 of the menstrual cycle.
Pituitary suppression was confirmed with a serum E2 150
pmol/L after 3 weeks of Nafarelin.
Once patients were downregulated, FSH (Gonal-F [Serono
Pharmaceuticals Ltd., Feltham, UK], Puregon [Organon Labora-
tories Ltd., UK], or Menopur [Ferring Pharmaceuticals Ltd., UK])
was started at a dose of 150–375 IU sub-cutaneously. The dose
was determined by the patient’s age, basal serum FSH level, and
previous ovarian response to gonadotrophins.
Ultrasound and serum monitoring of follicular response from day
9 of gonadotrophin stimulation was then performed.
HCG 6500 IU (Ovitrelle; Serono Pharmaceuticals Ltd., Feltham,
UK) was then administered subcutaneously, when at least three
leading follicles were 18 mm diameter.
Oocyte retrieval was performed 35 h following HCG administra-
tion.
IVF or ICSI was performed, as dictated by semen quality.
A maximum of two embryos were transferred to the uterus
trans-cervically 2 days later.
Luteal phase progesterone 400 mg Cyclogest (Shire Pharmaceu-
ticals Ltd., Basingstoke, UK) was then self-administered vaginally
from day before embryo transfer until day of pregnancy test.
A day 14 post-embryo transfer urinary-HCG pregnancy test was
then performed.
If pregnant, a transvaginal ultrasound 2 weeks later to confirm
clinical pregnancy was arranged.
Recombinant FSH preparations were used for ovarian stimula-
tion in 285 women, with only five using urinary-derived
preparations. ICSI was used as required.
2.1. Statistical analysis
Means were compared using the independent t-test or the
Mann–Whitney U-test for non-parametric data as appropriate.
Proportions were analyzed using the Chi-square test or Fisher’s
exact test as appropriate. Multiple logistic regression was used to
analyze dichotomous variables including rates of OHSS. All tests
performed used the SPSS statistics package (version 14.0 for
Windows; SPSS Inc., Chicago, IL, USA).
3. Results
The number of women in each group was: normal ovaries
(n = 111), PCO (n = 101), and PCOS (n = 78). Women with PCOS
were, on average, 1.5 years younger than those with normal
ovaries (p 0.05). There were no statistically significant
differences with respect to the duration of infertility or number
of previous live births (24 weeks) among the three groups
(Table 1).
Table 1
Characteristics of women with normal ovaries, ovulatory PCO and those with PCOS during their first IVF treatment cycle.
Characteristics Group 1: normal ovaries (n = 111) Group 2: PCO (n = 101) Group 3: PCOS (n = 78)
Age [years] 31.3 (3.3)*
30.4 (4.0) 29.8 (3.6)
Duration of subfertility [months] 40.4 (22.8) 37.4 (25.1) 34.8 (21.8)
No. of pts live births 24 weeks n [%] 15 (13.5%) 12 (11.9%) 15 (19.2%)
Means compared using independent t-test or Mann–Whitney U-test for non-parametric data. Results are means (SD) unless indicated. Only significant differences are
reported. SD, standard deviation.
*
P 0.05 compared to group 3.
Table 2
IVF outcome data of women with normal ovaries, ovulatory PCO and those with PCOS during their first IVF treatment cycle.
Outcome Group 1: normal ovaries (n = 111) Group 2: PCO (n = 101) Group 3: PCOS (n = 78)
Total dose of FSH [IU/L] 1996 (899)*
1595 (421) 1484 (410)
Peak E2 level [pmol/L] 5729 (3783)*
7507 (4148) 7430 (5466)
No. of follicles 14 mm on day 9 stimulation 4.2 (4.2)**
6.4 (5.5) 5.6 (5.1)
No. of follicles aspirated at oocyte collection 14.3 (8.1)*
24.5 (11.7) 24.3 (12.3)
No. of oocytes collected 10.5 (6.2)*
16.3 (7.7) 14.2 (8.1)
No. of oocytes fertilized 6.7 (4.3)**
9.8 (5.4) 8.5 (5.6)
Normal fertilization rate [%] 64.2%**
60.0% 59.6%
No. of embryos transferred 1.86 (0.5) 1.81 (0.6) 1.82 (0.7)
No. of embryos frozen 2.2 (3.1)***
4.1 (4.8) 3.1 (4.0)
PR/cycle started [%] 46% 52% 45%
CPR/cycle started [%] 44% 43% 37%
LBR/cycle started [%] 40% 38% 37%
Multiples
Twin [%] 31% 31% 28%
Triplet [%] 0 0 0
Means compared using independent t-test or Mann–Whitney U-test for non-parametric data. Results are means (SD) unless indicated. Proportions compared using Chi-
square test. Only significant differences are reported. FSH, follicle stimulating hormone; E2, estradiol level; PR, pregnancy rate/cycle started; CPR, clinical pregnancy rate/
cycle started; LBR, live birth rate/cycle started.
*
P 0.01 compared to groups 2 and 3.
**
P 0.05 compared to groups 2 and 3.
***
P 0.05 compared to group 2.
A. Swanton et al. / European Journal of Obstetrics Gynecology and Reproductive Biology 149 (2010) 68–71 69
3. The data were collated from each group for comparison and
statistical analysis (Table 2). There were no statistically signifi-
cant differences in any of the outcome measures between women
with PCO or PCOS. There were significantly higher numbers of
oocytes retrieved in the PCO and PCOS groups when compared to
women with normal ovaries. Similarly the peak estradiol levels,
number of follicles on day 9 stimulation and at oocyte collection,
number of embryos, and number of embryos frozen were all
significantly greater in the PCO and PCOS groups. Similar numbers
of embryos were replaced in each group. There were no
significant differences among the groups regarding clinical
pregnancy and live birth rates (per cycle started). There were
also no differences among the groups with regard to multiple
pregnancy.
OHSS admission rates were as reported in Table 3. There
were 28 (9.6%) cases of severe OHSS requiring hospital
admission. The number of severe OHSS cases was significantly
higher (p = 0.003) for women with PCO and PCOS when
compared to women with normal ovarian morphology. There
were no statistically significant differences in severe OHSS rates
between women with PCO and PCOS. The cycle cancellation rate
(either cancelled before oocyte retrieval due to concerns over
OHSS or had all embryos cryopreserved at 2PN stage) and the
total number of patients who had an adverse outcome (either
severe OHSS or cycle cancellation) were significantly higher in
the PCO and PCOS group (p 0.05 and p 0.01 respectively).
Only one of the eight patients who had their cycle cancelled
because of a significant risk of OHSS went on to develop the
condition. Seven patients were coasted, six of whom had PCO
and one with PCOS. Three out of these seven women had a
clinical pregnancy. Of the seven women who were coasted, three
went on to develop severe OHSS (all with PCO) and two were
subsequently pregnant.
Multiple logistic regression (Table 4) showed that the number
of oocytes retrieved, peak estradiol level, number of follicles at
oocyte collection, and ovarian morphology (patient group) were all
significantly correlated with regard to the patient developing
severe OHSS on univariate analysis. However, after controlling for
other variables in a multivariate regression model only ovarian
morphology remained highly associated with developing severe
OHSS.
4. Discussion
There were 5727 stimulated IVF treatment cycles commenced
at the Oxford Fertility Unit from November 1999 to November
2006 including 117 (2%) recorded admissions at Oxford with
severe OHSS. These rates are consistent with the literature [7,13].
However, this figure is possibly an underestimate as patients may
have underreported symptoms and/or may have been admitted to
other hospitals and not informed the IVF unit.
Our findings demonstrate that women with ovulatory PCO
develop similar rates of severe OHSS when compared to women
with PCOS, and this is significantly greater than women with
normal ovaries. This is partially explained by the fact that the
number of follicles, oocytes retrieved and peak estradiol levels
were all significantly increased in women with PCO and PCOS.
Despite a significant increase in the number of oocytes
retrieved and fertilized in women with PCO, the overall rates of
pregnancy or live birth are similar to women with normal ovaries.
These data are consistent with other findings but not with all
reports [14,15]. Engmann et al. evaluated IVF outcomes (up to
three cycles) in 46 women who had sonographic evidence of PCO,
but no clinical symptomatology associated with PCOS, compared
to 145 women with normal ovaries [15]. Adjusted for age, the odds
of achieving a pregnancy and live birth within three cycles of
treatment in a woman with PCO were 69% and 82% respectively
higher than those of a woman with normal ovaries. The authors
postulated that by retrieving more oocytes and achieving higher
fertilization rates, there could be greater embryo selection, and
therefore higher subsequent pregnancy rates, but our findings do
not confirm this.
Some limitations of this study include the fact that women in
group 1 (normal ovaries) were statistically older than women in
group 3 (PCOS). Women who are younger are at increased risk of
developing OHSS. Other potential confounders for developing
OHSS, such as body mass index and reason for subfertility, were
not collected or analyzed. Furthermore, there is potential for
selection bias as the diagnosis of severe OHSS (defined as that
requiring hospitalization) is subjective and dependant on an
individual clinician. A more objective definition, using haematocrit
concentrations 0.45 for example, may be more useful for
comparison.
Table 3
Number of patients admitted to hospital with severe OHSS or cycle cancellation.
Normal (n = 111) PCO (n = 101) PCOS (n = 78) P-valuea
No. of pts severe OHSS 3 (2.7%) 13 (12.6%) 12 (15.4%) 0.01
Cycle cancellation 2 (1.8%) 4 (3.9%) 2 (2.6%) NS
No. of patients coasted 0 6 (5.8%) 1 (1.3%) 0.05
Total adverse outcome 5 (4.5%) 17(16.5%) 14 (17.9%) 0.01
No. of coasted patients who developed severe OHSS N/A 3 (50%) 0 (0%) N/A
Results are n (%). NS, not significant; N/A, not applicable. Adverse outcomes include cycle cancellation before oocyte retrieval over concerns of OHSS, all embryos frozen, or
severe OHSS requiring hospitalization.
a
Fisher’s exact test between all three patient groups.
Table 4
Logistic regression analysis of IVF outcome variables and severe OHSS.
Variable Binary logistic regression P-value Multiple logistic regression P-value
Peak E2 level [pmol/L] 0.05 NS
No. of follicles 14 mm day 9 stimulation NS
No. of follicles at oocyte collection 0.05 NS
No. of oocytes collected 0.05 NS
Total dose of FSH [IU/L] NS
Patient group 0.01 0.05
Age [years] NS
NS, not significant. E2, estradiol level; FSH, follicle stimulating hormone.
A. Swanton et al. / European Journal of Obstetrics Gynecology and Reproductive Biology 149 (2010) 68–7170
4. Women with PCO require less total dose of gonadotrophin
stimulation than women with normal ovaries [16]. OHSS can be
very difficult to predict, and the severity or need for hospital
admission is very individual to a particular patient. However,
patients identified at risk, such as those with PCO, require close
monitoring during ovarian stimulation and need an appropriate
gonadotrophin drug dose to reduce the chance of an exaggerated
response. Studies have analyzed how to predict both the incidence
and the severity of OHSS [17–19]. There remains a debate in how
useful factors such as follicle number, number of oocytes retrieved
and serum estradiol levels actually are in preventing OHSS [20,21].
Other predictive factors such as vascular endothelial growth factor
have been analyzed in OHSS but this needs further evaluation [22].
One way to significantly reduce OHSS rates is to have stricter
criteria on when to cancel IVF cycles. This is in turn may affect
patients’ pregnancy rates and overall satisfaction with treatment.
Cycle cancellation and withholding the HCG trigger reduces the
chance of OHSS developing. However, the risk is not completely
eliminated as an endogenous surge of LH may occur, particularly in
cycles where GnRH agonists have not been employed, thereby
resulting in OHSS. Coasting involves withholding gonadotrophins
in cycles with excessive follicular stimulation and delaying HCG
administration, allowing serum E2 levels to fall, whilst continuing
GnRH agonist administration [23]. This may reduce early-onset
OHSS and aims to salvage an IVF cycle or ameliorate the severity of
OHSS, though the evidence for this is unclear [24]. Other methods
to reduce OHSS rates include using GnRH antagonist stimulation
protocols [25,26], albumin administration at the time of oocyte
collection [27], or considering ‘freeze-all’ cycles [28]. Elective
cryopreservation of all embryos at the 2PN stage does not reduce
the chance of developing early OHSS, but does significantly reduce
the chance of late onset OHSS.
Further studies assessing the underlying pathophysiology of
OHSS are needed, which may in turn lead to greater understanding
of how to prevent it developing.
An alternative technique of preventing OHSS is in vitro
maturation (IVM). This involves recovery of immature oocytes
from unstimulated ovaries: the oocytes are then matured in vitro
and subsequently used in IVF [29–31]. This is a fairly novel
technique and although success rates are promising it is not
currently employed routinely in the UK.
The use of insulin-sensitising agents such as metformin has been
shown to significantly reduce OHSS rates in patients with PCOS
though this has not yet been shown in patients with PCO [32,33].
Data from an ongoing randomized controlled trial from our unit are
awaited. Metformin administration before and during IVF treatment
should be considered in all patients with PCOS where there are no
contraindications. However, metformin is not currently licensed for
this indication and patients must be made aware of this.
5. Conclusion
Patients with PCO or PCOS are at similarly increased risk of
developing severe OHSS when compared to women with normal
ovaries. However pregnancy outcomes are similar among all three
groups. Strategies to reduce the risk of OHSS should be considered
in all women with PCO.
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