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the section, ˜Prevention of OHSS™. Therefore, it is recommended not to use
hCG for luteal phase support for all patients (Penzias, 2002; Guibert and
Olivennes, 2004; Rizk and Aboulghar, 2005).
29
OHSS AND CONCEPTION CYCLES




Table II.8 Incidence of pregnancy in patients with OHSS
Reproduced with permission from Rizk, B (1993). Progress in Obstetrics and
Gynecology. Churchill-Livingstone, Edinburgh, Volume 11, Chapter 18, pp. 311À49

Author Year Incidence (%) Number of patients Multiple pregnancies

Rabau 1967 42 6/14 2/6
Schenker and Weinstein 1978 40 10/25 5/10
Tulandi 1984 34.6 10/29 4/10
Golan 1988 91 10/11 1/10
Borenstein et al. 1989 35 14/39 3/14
Herman 1990 80 4/5 1/4
Forman 1990 88 7/8 2/7
Smitz 1990 70 7/10 3/7
Rizk 1991 57 12/21 5/12




OHSS AND CONCEPTION CYCLES
Frequency of OHSS and Conception Cycles
Rizk (1993a) found OHSS to be much more frequent in conception cycles
(Table II.8). In the early 1980s, Haning et al. (1983) found that OHSS was four
times more frequent when pregnancy occurs. The pregnancy rate in the reported
series of hyperstimulation varied from 34.6% to 91% (Rizk, 1993a). A high
incidence of multiple pregnancy (10À42%) was also observed. A statistically
signi¬cantly higher incidence of multiple pregnancies occurs speci¬cally in the
late OHSS patients compared with the non-OHSS patients (Mathur et al., 2000;
Papanikolaou et al., 2005). However, OHSS is very rarely reported in association
with multiple extrauterine pregnancy as bilateral ectopic or heterotopic
pregnancy (Rizk et al., 1990b, 1991d; Reyad et al., 1998; Shiao et al., 2004).
Papanikolaou et al. (2005) designed an observational study to determine
whether the onset pattern of OHSS is associated with the occurrence of
pregnancy and early pregnancy outcome. In their study, early OHSS occurred
in 53 patients, and late OHSS occurred in 60 patients. A total of 96.7% of the
late OHSS cases occurred in a pregnancy cycle and were more likely to be severe
than the early cases. The authors concluded that the early-onset pattern is
associated with exogenously administered hCG and a higher risk of pre-clinical
miscarriage, whereas late OHSS may be associated with the conception cycles,
especially multiple pregnancy cycles, and will most likely be severe
(Papanikolaou et al., 2005).


Duration of OHSS and Conception Cycles
The duration of OHSS is longer and its expression is more severe when
pregnancy ensues (Rizk 2001, 2002). Bider et al. (1989) found the average
30 EPIDEMIOLOGY OF OHSS: IATROGENIC AND SPONTANEOUS




hospitalization stay for pregnant patients with OHSS to be longer, compared to
non-pregnant patients. Koike et al. (2004) found that the severity of OHSS is
related to the number of conceptions, and this is re¬‚ected in the increased
number of days in the hospital. Papanikolaou et al. (2005) also observed that
late OHSS cases were more likely to be severe, and in fact accounted for 68% of
the total cases of severe OHSS.


SPONTANEOUS OHSS

Spontaneous OHSS is a rare event. Rizk (1993a, b) found rare reports of OHSS
in spontaneous cycles. However, over the last decade a large number of case
reports of spontaneous OHSS have been published, sometimes reoccurring
repeatedly in the same patients (Zalel et al., 1995; Lipitz et al., 1996; Regi et al.,
1996; Ayhan et al., 1996; Abu-Louz et al., 1997; DiCarlo et al., 1997; Nappi
et al., 1998; Todros et al., 1999; Pentz-Vidovic et al., 2000; Hee-Dong et al.,
2001; Jung and Kim, 2001; Chae et al., 2001). Most cases of spontaneous OHSS
have occurred in patients with PCOS, molar pregnancies and hypothyroidism
(Zalel et al., 1992; Nappi et al., 1998) and, very rarely, without any other
associated pathology (Chae et al., 2001).
The clinical presentation with ascites and pleural effusion is typical of
advanced ovarian cancer in the absence of any previous infertility treatment.
In the past, in many cases this has resulted in an exploratory laparotomy, as in
the case report of Ayhan et al. (1996). Surgery is generally not advised in the
treatment of OHSS (Rizk et al., 1990a; Rizk and Aboulgar, 1991, 1999), and yet,
in these extremely rare cases, surgery is often performed, based on an incorrect
diagnosis.
Jung et al. (2001) described a case of severe spontaneous OHSS with
magnetic resonance (MR) ¬ndings. MR scans showed bilateral symmetric
enlargement of the ovaries with multiple cystic changes, giving the classic
˜˜wheel-spoke™™ appearance. There was no de¬nite abnormally thickened or
enhanced wall, but there was internal hemorrhage in some chambers. The
authors emphasized the importance of careful diagnosis to differentiate
spontaneous OHSS from ovarian cystic neoplasms.


TIME COURSE DEVELOPMENT OF SPONTANEOUS OHSS

Spontaneous forms of OHSS have been generally reported to develop after
between 8 and 14 weeks amenorrhea, differing from iatrogenic OHSS, which
usually starts after between 3 and 5 weeks amenorrhea (Delbaere et al., 2004).


SPONTANEOUS OHSS AND hCG LEVELS

Most, if not all, cases of spontaneous OHSS are reported during pregnancy.
Endogenous hCG secreted by the trophoblast 7À8 days post-conception is an
31
HYPOTHYROIDISM AND OHSS




additional factor in sustaining and exacerbating OHSS (Zalel et al., 1992).
Spontaneous OHSS and elevated hCG levels have been described in multiple
pregnancies (Leis et al., 1978; Check et al., 2000) as well as in molar pregnancies
(Hooper et al., 1966; Moneta et al., 1974; Cappa et al., 1976; Ludwig et al.,
1998) and even singleton pregnancy (Rosen and Lew, 1991). On the other hand,
spontaneous OHSS and normal hCG levels have been reported by Zalel et al.
(1992) and Abu-Louz et al. (1997), and ¬nally, spontaneous OHSS and
low hCG has been reported by Todros et al. (1999).


RECURRENT OHSS

A series of cases of recurrent OHSS have been reported, with the development
of the syndrome in 2À6 consecutive pregnancies (Zalel et al., 1995;
Olatunbosun et al., 1996; Di Carlo et al., 1997; Edi-Osagie and Hopkins,
1997). Zalel et al. (1992) reported a case of OHSS in a spontaneous cycle in
a patient with PCOS. The same authors reported a recurrence of OHSS in
a spontaneous pregnancy in the same patient with PCOS (Zalel et al., 1995).


FAMILIAL OHSS

Di Carlo et al. (1997) reported the ¬rst case of spontaneous, familial, recurrent
OHSS, associated with high concentrations of renin and aldosterone. Both the
patient and her only sister had suffered from a similar condition in their
previous pregnancies. The authors suggested that similar cases of spontaneous
OHSS, when admitted to a surgical emergency department, may undergo
unnecessary surgical treatment by medical staff with no experience in
reproductive medicine. With the increasing awareness of these conditions,
more and more cases should be detected and reported. More recently,
mutations of the FSH receptor have been reported as the cause of recurrent
familial OHSS (Vasseur et al., 2003; Smits et al., 2003; Montanelli et al.,
2004a, b). These elegant cases explain not only the occurrence of familial OHSS
but also the occurrence of spontaneous cases without exogenous gonado-
trophins. The clinical presentation of four pregnancies associated with
spontaneous OHSS in a patient with a mutant FSH receptor has been
described by Smits et al. (2003) (Table II.9).


HYPOTHYROIDISM AND OHSS

OHSS has been reported in association with hypothyroidism (Rotmensch and
Scommegna, 1989; Nappi et al., 1998). Rotmensch and Scommegna (1989)
reported the ¬rst case of OHSS in a hypothyroid, non-pregnant patient with
Down™s syndrome. This case deserves a special mention because it antedates the
recent studies, where mutation of the FSH receptor was found to be the cause of
32
Table II.9 Clinical data of the four pregnancies associated with spontaneous ovarian hyperstimulation syndrome in a patient with mutant FSH
Reproduced with permission from Smits et al. (2003). N Eng J Med 349:760À6

Ovaries
Week of gestation HCG level Follow-up
at ¬rst ultrasound Aspect Size Symptoms IU/l Diagnosis Management Fetal outcome ultrasound

First pregnancy, 13 enlarged, NA NA NA theca lutein untreated term delivery, complete
multicystic cysts healthy girl, 2655 g regression
at 8 weeks
postpartum
Second pregnancy, 14 enlarged, 13‚14 cm ¬‚uid visible in NA spontaneous untreated in utero fetal death, complete
multicystic each pelvis and right OHSS, 41.5 weeks. 2800 g regression
hypochondrium Grade IV at 12 weeks
on ultrasonography postpartum
Third pregnancy, 9 enlarged, 14.5‚12.5 cm hydrothorax, 36, 200 spontaneous paracentesis nonviable fetus at complete
multicystic each abdominal distension (9 weeks); OHSS, 10 weeks 3 days regression at
with ascitic ¬‚uid 21, 350 Grade IV gestation; curettage 8 weeks after
visible in abdomen (10 weeks at 10 weeks 6 days miscarriage
and pelvis on 3 days);
ultrasonography 7430
(10 weeks
5 days)
Before pregnancy multiple 4.2‚3.2,
subcapsular 4.5‚3.5 cm
follicles,
5À8 mm
in diameter
Fourth pregnancy, 8 enlarged, 14‚16 cm hydrothorax, abdominal 101, 190 spontaneous paracentesis term delivery, complete
multicystic each distension with ascites; (8 weeks) OHSS, healthy boy, regression
thin ¬‚uid visible in abdomen Grade IV 2860 g at 8 weeks
hyperechogenic and pelvis on postpartum
follicles ultrasonography
33
THE ROLE OF AN OHSS REGISTRY




OHSS, and in at least two cases the mutant FSH receptors were sensitive to TSH
(Vasseur et al., 2003; Smits et al., 2003). A 21-year-old black, nulligravid
woman with Down™s syndrome presented with a two-week history of increasing
lower abdominal extension and pain. She denied nausea, vomiting, fever and
chills, vaginal bleeding and sexual activity. A pelvic ultrasonogram showed
multilateral ovarian cysts with a solid component on the right ovary measuring
10 ‚ 13.8 mm in diameter. Ascites was noted and a chest X-ray was within
normal limits. The urine pregnancy test was negative and the patient was
treated with levothyroxin and managed conservatively, and after 16 days her
symptoms markedly improved. The authors proceeded to do an exploratory
laparotomy because of the presence of the solid components on the ovary and
the previous reports of ovarian malignancies masquerading as OHSS. The
pathology showed benign follicular cysts. This case is interesting because the
patient did not receive exogenous ovarian stimulation and her endogenous
gonadotrophin levels were within normal limits. The authors suggested a causal
link between the patient™s profound hypothyroidism and the development of
OHSS because of the temporal relationship between the two and the marked
response to thyroid hormone replacement therapy. More recently, a case of
familial gestational hyperthyroidism, caused by a mutant thyrotropin receptor
hypersensitive to human chorionic gonadotrophin, has been reported (Rodien
et al., 1998).


SPONTANEOUS OHSS AND DVT

Todros et al. (1999) have reported a case of DVT associated with spontaneous
OHSS, which means that many of the thromboembolic cases seen with OHSS
are not related to exogenous gonadotrophins.


THE ROLE OF AN OHSS REGISTRY

The establishment of a reliable OHSS registry is of prime importance. It will
serve multiple purposes and have potential advantages for the care of all IVF
patients. It will be an accurate method for comparing the incidence of OHSS
if the demography of the patients is in the database. It will also identify
complications that could not be avoided, and in my opinion that is an
important aspect of patient care. Finally, guidelines for treatment could be
based on outcomes rather than impressions, particularly in critical cases.
So far, the collection of data on severe and critical OHSS cases has been an
informal task for many of us over the last two decades. The European Society
for Human Reproduction and Embryology (ESHRE) and the American Society
for Reproductive Medicine (ASRM) should take the lead in this important task.
A large group of international investigators have taken a lead in the last decade
in the study of pathophysiology and prevention of OHSS, and certainly would
be more than capable of expanding their role.
34 EPIDEMIOLOGY OF OHSS: IATROGENIC AND SPONTANEOUS




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