A role for estrogen monitoring for the prediction and prevention of OHSS was
suggested more than 30 years ago (Karam et al., 1973; Haning et al., 1985;
Fig. VI.1: Prediction of OHSS
120 PREDICTION OF OVARIAN HYPERSTIMULATION SYNDROME
Rizk and Aboulghar, 1991). Over the last three decades, reproductive
endocrinologists have been divided between those who valued the role of
estrogen monitoring for prevention of OHSS (Rizk and Aboulghar, 1991, 2005;
Smith and Cooke, 1991) and those who do not (Thomas et al., 2002). Haning et
al. (1983) compared plasma 17b-estradiol, 24-h urinary estriol glucuronide and
ultrasound as predictors of ovulation in 70 ovulation induction cycles. Plasma
estradiol was the best predictor of the hyperstimulation score. No case of OHSS
occurred when the plasma estradiol level was <1000 pg/ml, and the authors
considered 4000 pg/ml to be the level above which hCG should be withheld,
because OHSS occurred in all pregnancies when the estradiol level was
44000 pg/ml. Several authors reported severe OHSS with peak follicular
plasma estradiol levels well below 1500 pg/ml. On the other hand, only a
small fraction of patients with excessive estrogen concentrations will develop
Two studies from southern California highlight how the prevalence
of OHSS can vary among patients with similar estradiol levels. Asch et al.
(1991) reported severe OHSS in 5 of 13 IVF cycles where the serum estradiol on
the day of hCG was 46000 pg/ml. This gives a sensitivity of 83% and a
speci´¬ücity of 99%, although the positive predictive value was only 38%. When
the number of eggs aspirated was 430, the sensitivity was 83%, the speci´¬ücity
was 67% but the positive predictive value was only 23%. The number of
patients that met both criteria, estradiol 46000 pg/ml and 430 oocytes was not
given but analysis predicted an 80% chance of developing OHSS (Morris et al.,
1995). In order to determine the prediction of OHSS in patients meeting
both criteria, and to assess the effects of pregnancy, Morris et al. (1995)
compared two groups of patients, oocyte donors (n ┬╝ 72) and IVF patients
(n ┬╝ 67). They studied 139 IVF cycles between 1990 and 1993 in which estradiol
was over 4000 pg/ml, oocyte number 425, or both were elevated. There were no
severe cases of OHSS in the oocyte-donor group but six cases occurred in the IVF
group. In contrast to the results of Asch et al. (1991), they had only one OHSS
case in 10 patients with estradiol concentration 46000 pg/ml and 430 oocytes
(10%). The relative risk of OHSS in pregnancy was 12 with a con´¬üdence interval
of 2.18├Ç66.14. Morris et al. (1995) concluded that the risk of OHSS even
at high levels of stimulation is lower than previously believed. They believed
that oocyte donors had a very low risk of OHSS because of the absence of
VASCULAR ENDOTHELIAL GROWTH FACTOR
Vascular endothelial growth factor (VEGF) expression by luteinized granulosa
cells has been demonstrated in vitro and its extent differs widely between
individual patients (Rizk et al., 1997). The different mechanisms for reaching
different results and conclusions regarding the levels of VEGF in serum has
VASCULAR ENDOTHELIAL GROWTH FACTOR
been elegantly discussed by Delvigne (2004). These reasons, which have been
reviewed in detail in Chapter III, explain the variation in results among
different investigators who ascertain VEGF levels in order to predict OHSS
(Geva et al., 1999; DÔÇ™Ambrogio et al., 1999; Enskog et al., 2001; Mathur et al.,
2002). Even in the same patient, Tozer et al. (2004) observed a wide variation in
follicular ´¬‚uid levels of VEGF in follicles of the same size. There was also wide
variability among different patients.
While Agrawal et al. (1999) and Artini et al. (1998) found increased levels
of VEGF in follicular ´¬‚uid to be predictive of the development of OHSS
(Figures VI.2 and VI.3), other investigators have found that women at risk of
developing OHSS have signi´¬ücantly lower levels of VEGF in follicular ´¬‚uid,
and that lower levels are associated with good prognosis in patients who are
hyperresponders (Friedman et al., 1998; Pellicer et al., 1999; Quintana et al.,
Agrawal et al. (1999) performed one of the earlier studies to explore the
value of serum VEGF concentration during IVF cycles to predict the risk of
OHSS. They studied 107 women undergoing IVF. Mild OHSS developed in
10 women, moderate OHSS in seven women, and severe OHSS in three women.
Serum VEGF concentrations were higher in women in whom OHSS developed.
The increase in the VEGF concentration that occurred between the day of hCG
administration and the day of oocyte collection was termed the VEGF rise, and
proved to be an important marker of OHSS (Figures VI.2 and VI.3). The VEGF
rise was higher in women in whom OHSS developed. A higher VEGF predicted
all cases of OHSS and moderate/severe cases of OHSS with a sensitivity of 100%
and speci´¬ücity of 60%. A likelihood ratio test demonstrated that, by adding
the VEGF rise or the VEGF concentration on the day of oocyte collection to
a regression model as a continuance variable to the number of follicles, the
Fig. VI.2: Serum VEGF concentrations in IVF cycles with mild OHSS, moderate or severe
OHSS and without OHSS
Reproduced with permission from Agrawal et al. (1999). Fertil Steril 71:287├Ç93
122 PREDICTION OF OVARIAN HYPERSTIMULATION SYNDROME
Fig. VI.3: Changes in serum VEGF concentrations and doppler blood ´¬‚ow velocity in
patients with and without OHSS
Reproduced with permission from Agrawal et al. (1999). Fertil Steril 71:287├Ç93
estradiol concentration and the presence of polycystic ovaries signi´¬ücantly
contributed to predicting the risk of OHSS.
Free Serum VEGF for the Prediction of OHSS
Ludwig et al. (1999) compared free serum VEGF levels in 10 patients who
developed severe OHSS, and 15 control patients who did not develop
OHSS. A positive predictive value of 75% and negative predictive value of
92% was obtained, using a cutoff level of 200 pg/ml on the day of hCG
administration. The possible predictive role of free VEGF should be inves-
SERUM AND FOLLICULAR FLUID CYTOKINE LEVELS IN
THE PREDICTION OF OHSS
Chen et al. (2000) examined the role of serum and follicular ´¬‚uid cytokines and
VEGF in the prediction of OHSS. The study group consisted of 12 women who
developed moderate (n ┬╝ 7) or severe (n ┬╝ 5) OHSS. The authors chose two
control groups which consisted of 12 high-risk and 12 low-risk women in
whom OHSS did not develop. Serum was collected on the days of hCG, oocyte
retrieval and embryo transfer, and then serum and follicular ´¬‚uid concentra-
tions of IL-6 and IL-8, TNFa and VEGF were determined. Follicular ´¬‚uid
concentration of IL-6 (p ┬╝ 0.026) at the time of oocyte retrieval and serum
levels of IL-8 at the time of embryo transfer were signi´¬ücantly higher
(p ┬╝ 0.017) in the OHSS group than in the control groups. Serum VEGF and
TNFa levels were not statistically signi´¬ücant for either group when compared
VON WILLEBRAND FACTOR
to controls. The authors concluded that follicular ´¬‚uid IL-6 at the time of
oocyte retrieval and serum IL-8 at the time of embryo transfer may serve as
early predictors of this syndrome.
VON WILLEBRAND FACTOR
Todorow et al. (1993) were the ´¬ürst to suggest the possible involvement of von
Willebrand factor (vWF) in the pathophysiology of OHSS. They performed a
retrospective study to evaluate the possible role of endothelial and extracellular
factors in the pathophysiology of the syndrome. Plasma changes of vWF were
correlated with the clinical condition of the hyperstimulated patients. Basal
values of patients who did and did not develop OHSS were not different. Mean
values were signi´¬ücantly different in the two groups on the day preceding
oocyte retrieval (Figure VI.4). A consistent increase in the OHSS group lasted
after embryo transfer even into the late corpus luteum phase. The subtle
changes in capillary permeability always preceded the clinical signs such as
ascites, hemoconcentration, hypoproteinemia and pleural effusion. The authors
considered that vWF provides an additional prognostic marker for early
recognition and monitoring of OHSS.
Ogawa et al. (2001) retrospectively evaluated the vWF and VEGF serum
levels on the days of oocyte retrieval and embryo transfer in 46 women
who developed early-onset OHSS. Severe, moderate and mild OHSS occurred
in 13, 14 and 19 patients respectively. There were inconsistent changes in
the VEGF levels during oocyte retrieval and embryo transfer. However, the
net increase in serum vWF showed an increase in absolute value at the
time of embryo transfer that paralleled the severity of OHSS. The authors
suggested that the rise of serum levels of vWF occurs prior to clinical mani-
festation of OHSS in patients with severe OHSS, but not in patients with
Fig. VI.4: vWf antigen in IVF cycles: control vs. OHSS
Reproduced with permission from Todorow et al. (1993). Hum Reprod 8:2039├Ç46
124 PREDICTION OF OVARIAN HYPERSTIMULATION SYNDROME
Enskog et al. (2000) found that peripheral blood concentrations of inhibin-B
are elevated during gonadotrophin stimulation in patients who later develop
OHSS, and inhibin-A concentrations are elevated after OHSS onset.
FOLLICULAR MONITORING BY ULTRASOUND
Ultrasound monitoring is the cornerstone of prediction of OHSS (Rizk, 1993).
Baseline Necklace Sign Appearance
The diagnosis of polycystic ovaries at ultrasound examination (the necklace
sign) is essential for prediction of OHSS (Rizk and Smitz, 1992). It improved
the prediction of OHSS to 79% in a Belgian multicenter study (Delvigne et al.,
Number and Size of Follicles During Ovarian Stimulation
Ultrasound is widely used for monitoring follicular development in assisted
conception (Rizk and Nawar, 2004). The number, size and pattern of
distribution of the follicles are important in the prediction of OHSS. Tal
et al. (1985) found a positive correlation between the mean number of
immature follicles and OHSS. One of the most-often-quoted articles in
reference to prediction is that by Blankenstein et al. (1987). They stated that
a decrease in the fraction of the mature follicles and an increase in the fraction
of the very small follicles correlated with an increased risk of the development
of severe OHSS.
Baseline Ovarian Volume and the Prediction of OHSS
Danninger et al. (1996) studied the baseline ovarian volume prior to
stimulation, to investigate whether it would be a suitable predictor for the
risk of OHSS. They performed three-dimensional volumetric ultrasound
assessment of the ovaries prior to ovarian stimulation and on the day of hCG
injection. There was a signi´¬ücant correlation between the baseline ovarian
volume and the subsequent occurrence of OHSS. The authors suggested that
volumetry of the ovaries could help to detect patients at risk. Lass et al. (2002)
studied whether ovarian volume in the early follicular phase of WHO Group II
anovulatory patients would predict the response to ovulation induction with
gonadotrophins. They analyzed retrospective data from two prospective
randomized multicenter studies, including 465 patients undergoing ovulation
induction. WHO Group II anovulatory women with medium-sized or large
ovaries undergoing low-dose gonadotrophin stimulation for ovulation induc-
tion would have a higher risk for OHSS than women with small ovaries.
FOLLICULAR MONITORING BY ULTRASOUND
Low Intra-vascular Ovarian Resistance
Moohan et al. (1997) assessed the intra-ovarian blood ´¬‚ow in relation to the
severity of OHSS in 30 patients with OHSS after embryo transfer who also had
sonographic evidence of ascites. The authors measured the resistance to blood
´¬‚ow within the ovaries of 11 patients with severe OHSS and 19 patients with
mild OHSS by using transabdominal ultrasonography with color ´¬‚ow and
pulsed Doppler imaging. The pulsatility index (PI), resistance index (RI) and
the systolic├Çdiastolic ratio, all measures of downstream vascular impedance,
were signi´¬ücantly lower in severe OHSS patients. In patients with RI < 0.48,
more than two thirds had pleural effusion. In patients with either PI < 0.75 or
S-D < 1.92, pleural effusion was observed in more than one-half. The blood
´¬‚ow velocity did not differ signi´¬ücantly between the two groups despite the fact
that there were changes in vascular impedance. A close correlation was observed
between the OHSS severity and the intra-ovarian blood ´¬‚ow resistance.
The authors suggested that measurements of intra-ovarian vascular resistance
in patients undergoing controlled ovarian hyperstimulation may help in
predicting those patients at particular risk of developing OHSS.
Genetic Prediction of OHSS: Severity, but not Occurrence
It is greatly hoped that studies on the FSH receptor genotype will be able to
predict in advance patients at risk of developing OHSS. One such important
study, evaluating FSH receptor genotype, concluded that it was not possible to
predict which patients would develop OHSS but FSH receptor genotype could
be a predictor of severity in OHSS patients (Daelemans et al., 2004).
Prediction of OHSS by One or More Risk Factors
The use of one or more risk factors for the prediction of OHSS has been
extensively investigated (Delvigne et al., 1993a, b; Agrawal, 2003; DÔÇ™Angelo et
al., 2004). DÔÇ™Angelo et al. (2004) assessed the value of different serum estradiol
cut-off levels for predicting OHSS. They studied 40 women with OHSS and 40
control patients in a retrospective case-controlled study. Serum estradiol level
of 3354 pg/ml on day 11 of ovarian stimulation gives a sensitivity and speci´¬ücity
of 85% for detection of women at risk of developing OHSS. Markers such as
serum estradiol concentrations, the number of follicles on the day of hCG
administration, the presence of polycystic ovaries (PCO) and the number of
oocytes retrieved, each predicts less than a quarter of cases of the syndrome
(Agrawal, 2003). On the other hand, a combination of pretreatment diagnosis
of PCO, along with the number of follicles on the day of hCG administration
and a ÔÇ˜ÔÇ˜VEGF riseÔÇ™ÔÇ™ in serum gives the highest prediction rate for the
development of OHSS.
The considerable overlap of values for different parameters between
OHSS and control patients makes any single variable inef´¬ücient for a reli-
able risk prediction (Delvigne, 2004). Multiple discriminate analysis, using a
126 PREDICTION OF OVARIAN HYPERSTIMULATION SYNDROME
combination of variables, was studied in order to increase predictive power and
decrease false negative prediction (Delvigne et al., 1993b). In their study of 128
OHSS patients and 256 controls, a prediction of 78.5%, with a corresponding
false negative rate of 18.1%, was obtained for OHSS under post-retrieval
conditions using log estradiol concentration, slope of log estradiol increment,
gonadotrophin dosage, number of oocytes retrieved and LH/FSH ratio in the
formula. However, effective prevention of OHSS implies the ability to withhold
hCG injection, therefore, Delvigne et al. (1993a, b) devised a formula for the
prediction of OHSS utilizing preoocyte retrieval conditions. That formula
yielded a prediction rate of 76.1% with a false negative rate of 18.1%.
Ovarian Hyperstimulation Syndrome Information for Patients
Ovarian hyperstimulation syndrome (OHSS) is an uncommon complication
that may result from the use of fertility injections during the course of
treatment. It can occur in one to two of every 100 women undergoing
treatment for infertility by in vitro fertilization. Awareness of symptoms is very
important as a patient, because more interventions can be carried out earlier
rather than later.
Patients at risk of ovarian hyperstimulation are young women with
polycystic ovaries. Polycystic ovaries can be detected by ultrasound scans
prior to the treatment cycle. If, during treatment, further ultrasound scans
suggest that the ovaries are overresponding, then this matter would be
discussed with you.
Usually the symptoms of OHSS occur a few days after the injection of hCG
is given to help in releasing the eggs. The symptoms may worsen and last longer
if a pregnancy occurs. In OHSS the ovaries are enlarged and swell, and ´¬ünally,
´¬‚uid leaks into the abdomen. The leakage of ´¬‚uid results in dehydration and
the risk of thrombosis or clotting in the veins, and rarely kidney damage. The
symptoms we want you to look for are nausea and vomiting, abdominal
discomfort and bloating, and abdominal swelling. If you become short of
breath or develop extreme thirst and pass only small amounts of concentrated
dark urine, you need to immediately contact the IVF center and explain these
symptoms. During all times, you should drink plenty of clear ´¬‚uids, such as
Sprite. You can also drink milk and take Tylenol as a pain killer, and avoid
strenuous physical activity. Keep with you at all times the hospital number for
out of hours and emergency situations. The art and the science is to intervene
early to prevent the situation from getting worse.
Agrawal R, Tan SL, Wild S et al. (1999). Serum vascular endothelial growth factor
concentrations in in-vitro fertilization cycles predict the risk of ovarian hyperstimu-
lation syndrome. Fertil Steril 71:278├Ç93.
Agrawal R (2003). WhatÔÇ™s new in the pathogenesis and prevention of ovarian
hyperstimulation syndrome? Hum Fertil (Camb) 3:112├Ç15.
Artini PG, Fasciani A, Monti M et al. (1998). Changes in vascular endothelial growth
factor levels and the risk of ovarian hyperstimulation syndrome in women enrolled in
an in vitro fertilization program. Fertil Steril 70:560├Ç4.
Asch RH, Li HP, Balmaceda JP et al. (1991). Severe ovarian hyperstimulation syndrome in
assisted reproductive technology: de´¬ünition of high risk groups Hum Reprod
Blankenstein J, Shalev J, Saadon T et al. (1987). Ovarian hyperstimulation syndrome
prediction by number and size of preovulatory ovarian follicles. Fertil Steril
Chen CD, Chen HF, Lu HF et al. (2000). Value of serum and follicular ´¬‚uid cytokine
pro´¬üle in the prediction of moderate to severe ovarian hyperstimulation syndrome.
Hum Reprod 15:1037├Ç42.
DÔÇ™Ambrogio G, Fasciani A, Monti M et al. (1999). Serum vascular endothelial growth
factor levels before starting gonadotrophin treatment in women who have devel-
oped moderate forms of ovarian hyperstimulation syndrome. Gynecol Endocrinol
DÔÇ™Angelo A, Davies R, Salah E et al. (2004). Value of the serum estradiol level for
preventing ovarian hyperstimulation syndrome: a retrospective case control study.
Fertil Steril 81:332├Ç6.
Daelemans C, Smits G, de Maertelaer V et al. (2004). Prediction of severity of symptoms
in iatrogenic ovarian hyperstimulation syndrome by follicle stimulation hormone
receptor Ser 680 Asn polymorphism. J Clin Endocrinol Metab 89:6310├Ç15.
Danninger B, Brunner M, Obruca A et al. (1996). Prediction of ovarian hyperstimulation
syndrome of baseline ovarian volume prior to stimulation. Hum Reprod 11:1597├Ç9.
Delvigne A (2004). Epidemiology and pathophysiology of ovarian hyperstimulation
syndrome. In (Gerris G, Olivennes F, De Sutter P, Eds), Assisted Reproductive
Technologies: Quality and Safety. New York: Parthenon Publishing, Chapter 12,
Delvigne A, Demoulin A, Smitz J et al. (1993a). The ovarian hyperstimulation syndrome
in in-vitro fertilization: a Belgian multicenter study. I. Clinical and biological features.
Hum Reprod 8:1353├Ç60.
Delvigne A, Dubois M, Battheu B et al. (1993b). The ovarian hyperstimulation syndrome
in in-vitro fertilization: a Belgian multicenter study. II. Multiple discriminant analysis
for risk prediction. Hum Reprod 8:1361├Ç6.
Enskog A, Nilsson L & Brannstrom M (2000). Peripheral blood concentrations of inhibin
B are elevated during gonadotrophin stimulation in patients who later develop
ovarian OHSS and inhibin A concentrations are elevated after OHSS onset. Hum
Enskog A, Nilsson L & Brannstrom M (2001). Plasma levels of free vascular endothelial
growth factor (165) (VEGF 165) are not elevated during gonadotrophin stimulation
in in-vitro fertilization (IVF) patients developing ovarian hyperstimulation syndrome
(OHSS): results of a prospective cohort study with matched controls. Eur J Obstet
Gynecol Reprod Biol 96:196├Ç201.
Friedman CI, Seifer DB, Kennard EA et al. (1998). Elevated level of follicular ´¬‚uid vascular
endothelial growth factor is a marker of diminished pregnancy potential. Fertil Steril
Geva E, Amit A, Lessing JB et al. (1999). Follicular ´¬‚uid levels of vascular endothelial
growth factor. Are they predictive markers for ovarian hyperstimulation syndrome?
J Reprod Med 44:91├Ç6.
Haning RV Jr, Austin CW, Carlson IH et al. (1983). Plasma estradiol is superior to
ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation
during induction of ovulation with menotropins. Fertil Steril 40:31├Ç6.
Haning RV, Strawn EY & Nolten WE (1985). Pathophysiology of the ovarian
hyperstimulation syndrome. Obstet Gynecol 66:220├Ç4.
128 PREDICTION OF OVARIAN HYPERSTIMULATION SYNDROME
Karam KS, Taymor ML & Berger MJ (1973). Estrogen monitoring and the prevention of
ovarian overstimulation during gonadotrophin therapy. Am J Obstet Gynecol