LINEBURG


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Fig. I.1: Multiple follicular cysts in the ovaries of a hyperstimulated patient




1
2 CLASSIFICATION OF OVARIAN HYPERSTIMULATION SYNDROME




Fig. I.2: Ascites in a hyperstimulated patient


Mansour (2003) have reviewed the classi¬cations used for OHSS over the
last four decades (Table I.1).
A group of pioneers in ovulation induction observed what they called
adverse events in the ¬rst 100 patients undergoing ovulation induction (Rabau
et al., 1967). This led them to propose the ¬rst classi¬cation of OHSS. This was
later reorganized by Schenker and Weinstein (1978) into three main clinical
categories and six grades. Golan et al. (1989) introduced a new classi¬cation of
three categories and ¬ve grades of OHSS. This was later modi¬ed by further
dividing the severe form into two subgroups (Navot et al., 1992). The most
recent classi¬cations with further modi¬cations were introduced in 1999
by Rizk and Aboulghar (1999).


THE FIRST CLASSIFICATION OF OHSS

Rabau et al. (1967) proposed the ¬rst classi¬cation of OHSS which
combined both laboratory and clinical ¬ndings (Table I.2). The authors
reported one of the original series of ovulation induction in 110 patients
who had undergone 202 courses of treatment. In most instances, hyper-
stimulation was limited to increased estrogen and pregnanediol urinary
excretion values without palpable cysts or enlargement of the ovaries. In
seven cases the authors noted ovarian enlargement or cysts, low abdominal
pain and/or distention and nausea (Group 3, Table I.3). Five of the seven
patients in Group 3 also vomited or complained of diarrhea (Group 4).
The authors classi¬ed Groups 3 and 4 as mild adverse reactions. They
hospitalized these two groups to prevent exacerbation or further complica-
tions (Mozes et al., 1965). In seven patients, the clinical presentation was
enlargement of the ovaries, distention, cysts, nausea, and diarrhea and ascites.
Four of these seven patients also had hydrothorax (Group 5). Three patients
Table I.1 Classi¬cations of ovarian hyperstimulation syndrome (1967À1999)
Reproduced with permission from Aboulghar and Mansour (2003). Hum Reprod Update 9:275À89

Study Mild Moderate Severe

Rabau et al. (1967) Grade 1: estrogen 4150 mg/24 h Grade 3: grade 2 þ Grade 5: grade 4 þ Grade 6: grade 5 þ changes in
and pregnanediol 410 mg/24 h con¬rmed palpable ascites and possibly blood volume, viscosity and
Grade 2: þ enlarged ovaries and cysts and distended hydrothorax coagulation time
possibly palpable cysts abdomen
Grade 1 and 2 were not included Grade 4: grade 3 þ
under the title of mild OHSS vomiting and
possibly diarrhea

Schenker and Grade 1: estrogen 4150 mg/24 h Grade 3: grade 2 þ Grade 5: grade 4 þ Grade 6: marked
Weinstein (1978) and pregnanediol 410 mg/24 h abdominal distension large ovarian cysts, hemoconcentration þ increased
Grade 2: grade 1 þ enlarged Grade 4: grade 3 ascites and/or blood viscosity and possibly
ovaries, sometimes small cysts þ nausea, vomiting hydrothorax coagulation abnormalities
and/or diarrhea

Golan et al. (1989) Grade 1: abdominal distension Grade 3: grade 2 þ Grade 4: grade 3 þ Grade 5: grade 4 þ
and discomfort ultrasound clinical evidence of hemoconcentration, increased blood
Grade 2: grade 1 þ nausea, evidence of ascites ascites and/or viscosity, coagulation abnormality
vomiting and/or diarrhea, hydrothorax and and diminished renal perfusion
enlarged ovaries 5À12 cm breathing dif¬culties

À
Navot et al. (1992) Severe OHSS: variable Critical OHSS: variable enlarged
enlarged ovary: massive ovary: tense ascites + hydrothorax:
ascites + hydrothorax: hemocrit 455%; WBC 425 000;
hemocrit 445%: oliguria: creatinine 41.6; creatinine
WBC 415 000; clearance <50 ml/min; renal failure;
oliguria: creatinine 1.0À1.5; thromboembolic phenomena; adult
creatinine clearance ¸50 ml/min; respiratory distress syndrome
liver dysfunction; anasarca

Rizk and Aboulghar À Discomfort, pain, Grade A: dyspnoea, Grade B: grade A þ Grade C: complications as
(1999) nausea, distension, oliguria, nausea, vomiting, massive tension ascites, respiratory distress syndrome,
ultrasonic evidence diarrhea, abdominal pain, markedly enlarged ovaries, renal shut-down or venous
of ascites and clinical evidence of ascites, severe dyspnea and thrombosis
enlarged ovaries, marked distension of marked oliguria, increased
normal abdomen or hydrothorax, hematocrit, elevated
hematological ultrasound showing large serum creatinine and
and biological ovaries and marked ascites, liver dysfunction




3
pro¬les normal biochemical pro¬le
4 CLASSIFICATION OF OVARIAN HYPERSTIMULATION SYNDROME




Table I.2 First classi¬cation of OHSS
Reproduced with permission from Rabau et al. (1967). Am J Obstet Gynecol
98:92À8

Adverse reactions

No reaction* Mild** Severe{

Laboratory and clinical ¬ndings 1 2 3 4 5 6

Estrogens 4150 mg/24 h þ þ þ þ þ þ
Pregnanediol 410 mg/24 h þ þ þ þ þ þ
Enlarged ovaries þ þ þ þ þ
Palpable cysts ? þ þ þ þ
Distension of abdomen þ þ þ þ
Nausea þ þ þ þ
Vomiting þ þ þ
Diarrhea ? þ þ
Ascites þ þ
Hydrothorax ? þ
Changes in blood volume, þ
viscosity and coagulation time

* No treatment required
** Required observation
{
Required hospitalization


from Group 5 subsequently showed changes in blood volume, viscosity and
hypercoagulability (Group 6). Groups 5 and 6 needed hospitalization and
therapeutic control of blood volume viscosity and coagulation time, as
well as evacuation of ¬‚uid cavities. Rabau et al. (1967) reclassi¬ed Groups 5
and 6 as severe adverse reactions and reported the serious complications
and management in a much quoted publication (Mozes et al., 1965).


REORGANIZATION OF OHSS CLASSIFICATION

Schenker and Weinstein (1978) reorganized the classi¬cation by Rabau et al.
(1967) into three main clinical categories and six grades according to the
severity of symptoms and signs, and laboratory ¬ndings.

(1) Mild hyperstimulation
Grade 1, de¬ned by laboratory ¬ndings of estrogen levels above 150 mg/
24 h and pregnanediol excretion above 10 mg/24 h
Grade 2, in addition, includes enlargement of ovaries; sometimes small
cysts are present
Table I.3 Mild and severe cases of OHSS
Reproduced with permission from Rabau et al. (1967). Am J Obstet Gynecol 98:92À8

Mild Severe

Ampules of hCG Ampules of hCG
Diagnosis Case Pergonal (IU) Remarks Case Pergonal (IU) Remarks

Primary amenorrhea Ge. E.20/31 25 25 000 Pregnancy Do. M. 108/199 22 25 000 pregnancy
À
Le. R. 63/108 28 26 000
À À
Secondary amenorrhea Ge. P. 21/32 55 29 000 Ge. P. 21/34 73 15 000
Secondary amenorrhea; Ki. A. 59/149 14 25 000 pregnancy
MAP þ
À
secondary amenorrhea Sh. M. 72/121 28 29 000
and galactorrhea
Postpartum amenorrhea Lo. S. 40/67 19 25 000 Pregnancy Bi. F. 11/17 3460 21 500 quadruplet
and galactorrhea Ba. A. 13/21 25 000 abortion
À À
Anovulation Iv. B. 1/1 Hi. E. 89/163 2927 20 000 Be. Z. 19/29 20 10 000
25 000
À
Proliferative follicular Po. A. 53/90 20 25 000 twin pregnancy
phase




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6 CLASSIFICATION OF OVARIAN HYPERSTIMULATION SYNDROME




(2) Moderate hyperstimulation
Grade 3, in addition to elevated urinary steroid levels and ovarian cysts,
abdominal distension is present
Grade 4, nausea, vomiting and/or diarrhea are also observed

(3) Severe hyperstimulation
Grade 5, in addition to the above, the ovarian cysts are large and ascites
and/or hydrothorax are present
Grade 6, marked hemoconcentration with increased blood viscosity may
result in coagulation abnormalities


MODERNIZATION OF THE OHSS CLASSIFICATION

Golan et al. (1989) proposed a new classi¬cation in which 24-hour urinary
assays of hormones became obsolete, and subsequently estrogen and preg-
nanediol assays were also omitted. Nausea, vomiting and abdominal distension
were relocated from moderate to mild OHSS, and then moderate OHSS was no
longer divided into two different grades as in the previous speci¬cation; it
mainly added ultrasound evidence of ascites to the features of Grade 2 OHSS.
In my opinion, this was an important addition. Severe OHSS was classi¬ed into
two grades (Grade 4 and 5), which were similar to the previous classi¬cation.

(1) Mild OHSS
Grade 1, abdominal distension and discomfort
Grade 2, features of grade 1 plus nausea, vomiting and/or diarrhea; ovaries
are enlarged from 5 to 12 cm

(2) Moderate OHSS
Grade 3, features of mild OHSS plus ultrasonic evidence of ascites

(3) Severe OHSS
Grade 4, features of moderate OHSS plus evidence of ascites and/or
hydrothorax and breathing dif¬culties
Grade 5, all of the above, plus change in the blood volume, increased
blood viscosity due to hemoconcentration, coagulation abnormality, and
diminished renal perfusion and function


DESIGNATION OF CRITICAL OHSS
AS A SPECIAL ENTITY

Navot et al. (1992) suggested making a distinction between severe and life-
threatening OHSS by dividing it into two subgroups. Severe OHSS was
characterized by variably enlarged ovaries, massive ascites and/or hydrothorax,
hematocrit over 45%, WBC 4 15 000, oliguria, creatinine of 1.0À1.5 and
7
CLINICAL CLASSIFICATION OF OHSS




creatinine clearance of ¸50 ml/min. Furthermore, generalized edema and liver
dysfunction were considered to be signs of severe OHSS. Critical OHSS was
characterized by enlarged ovaries, tense ascites, hematocrit of over 55%, WBC
¸25 000, oliguria, creatinine ¸1.6 and creatinine clearance <50 ml/min. Renal
failure, thromboembolic phenomena and adult respiratory distress syndrome
(ARDS) constituted critical OHSS. This subdivision was important from both
clinical and prognostic aspects. The group of patients labeled as critical OHSS
should be treated under very close supervision in an intensive care setting.


CLINICAL CLASSIFICATION OF OHSS

More recently, Rizk and Aboulghar (1999) classi¬ed the syndrome into
only two categories, moderate and severe. The purpose of this classi¬cation
is to categorize patients with OHSS into more-de¬ned clinical groups
that correlate with the prognosis of the syndrome. This would be ideal
from an epidemiological point of view to set a registry for these cases.
Furthermore, treatment could be advised depending on which group the
patient belongs to.
The mild category of OHSS, as in previous classi¬cations by Rabau et al.
(1967) and Golan et al. (1989), was omitted from our new classi¬cation, as this
occurs in the majority of cases of ovarian stimulation and does not require
special treatment. The great majority of cases of OHSS presenting with
symptoms belong to the moderate categories of OHSS. In addition to the
presence of ascites on ultrasound, the patients™ complaints are usually limited to
mild abdominal pain and distension, and their hematological and biochemical
pro¬les are normal.
Finally, how does this classi¬cation guide treatment of the syndrome? Our
new classi¬cation can be correlated with the treatment protocol and prognosis
more clearly. Severe OHSS Grade C, which is critical, would be treated in an
intensive care setting; whereas severe OHSS Grade B would be treated in an
inpatient hospital setting with expert supervision. Severe OHSS Grade A could
be treated in an inpatient or outpatient setting, depending on the physician™s
comfort, the patient™s compliance and the medical facility. Moderate OHSS
could be treated on an outpatient basis with extreme vigilance.

(1) Moderate OHSS
Discomfort, pain, nausea, abdominal distension, no clinical evidence of
ascites, but ultrasonic evidence of ascites and enlarged ovaries, normal
hematological and biological pro¬les

(2) Severe OHSS
Grade A
Dyspnea, oliguria, nausea, vomiting, diarrhea, abdominal pain
Clinical evidence of ascites plus marked distension of abdomen or
hydrothorax
8 CLASSIFICATION OF OVARIAN HYPERSTIMULATION SYNDROME




Ultrasound scan showing large ovaries and marked ascites
Normal biochemical pro¬les

Grade B
All symptoms of grade A, plus:
Massive tension ascites, markedly enlarged ovaries, severe dyspnea and
marked oliguria
Biochemical changes in the form of increased hematocrit, elevated serum
creatinine and liver dysfunction

Grade C
OHSS complicated by respiratory distress syndrome, renal shut-down or
venous thrombosis


EARLY AND LATE OHSS

OHSS in patients undergoing controlled ovarian hyperstimulation has been
observed to occur in two distinct forms: early onset and late onset, with
possibly different predisposing factors. Early OHSS presents 3 to 7 days after
the ovulatory dose of hCG, whereas late OHSS presents 12 to 17 days after
hCG. Early OHSS relates to ˜˜excessive™™ preovulatory response to stimulation,
whereas late OHSS depends on the occurrence of pregnancy, is more likely to
be severe, and is only poorly related to preovulatory events (Dhal-Lyons et al.,
1994; Mathur et al., 2000).


SPONTANEOUS AND IATROGENIC OHSS

Traditionally, it has always been stated that OHSS is the most serious iatrogenic
complication of ovulation induction. Interestingly, over the last decade, a
signi¬cant number of reports have been published about spontaneous OHSS
without any pharmacological intervention. Most of these cases have been
observed in multiple pregnancies (Check et al., 2000) or hyaditiform moles
notorious for high hCG values (Ludwig et al., 1998). Some cases were
associated with hypothyroidism and the possibility that the high levels of
TSH could stimulate the ovaries has been raised (Nappi et al., 1998). A series of
cases where recurrent OHSS occurred (Zalel et al., 1995; Olatunbosun et al.,
1996; Di Carlo et al., 1997) have been reported. More recently, mutations
of FSH receptors have been implicated as a cause for spontaneous OHSS
(Vasseur et al., 2003; Smits et al., 2003; Montanelli et al., 2004). Spontaneous
forms of OHSS were generally reported to develop between 8 and 14 weeks of
amenorrhea. In contrast, iatrogenic OHSS usually starts between 3 and 5 weeks
of amenorrhea.
9
REFERENCES




REFERENCES

Aboulghar MA & Mansour RT (2003). Ovarian hyperstimulation syndrome: classi¬cations
and critical analysis of preventive measures. Hum Reprod Update 9:275À89.
Check JH, Choe JK & Nazari A (2000). Hyperreactio luteinalis despite the absence of
a corpus luteum and suppressed follicle stimulation concentrations in a triplet
pregnancy. Hum Reprod 15:1043À5.
Dahl-Lyons CA, Wheeler CA, Frishman GN et al. (1994). Early and late presentation of the
ovarian hyperstimulation syndrome: two distinct entities with different risk factors.
Hum Reprod 9:792À9.
Di Carlo C, Bruno PA, Cirillo D et al. (1997). Increased concentrations of renin,
aldosterone and Ca125 in a case of spontaneous, recurrent, familial, severe ovarian
hyper-stimulation syndrome. Hum Reprod 12:2115À17.
Golan A, Ron-El R, Herman A et al. (1989). Ovarian hyperstimulation syndrome: an
update review. Obstet Gynecol Surv 44:430À40.
Ludwig M, Gembruch U, Bauer O et al. (1998). Ovarian hyperstimulation syndrome
(OHSS) in a spontaneous pregnancy with a fetal and placental triploidy: information
about the general pathophysiology of OHSS. Hum Reprod 13:2082À7.
Mathur RS, Akande AV, Keay SD et al. (2000). Distinction between early and late ovarian
hyperstimulation syndrome. Fertil Steril 73:901À7.
Montanelli L, Delbaere A, Di Carlo C et al. (2004). A mutation in the follicle-stimulating
hormone receptor as a cause of familial spontaneous ovarian hyperstimulation
syndrome. J Clin Endocrinol Metab 89:1255À8.
Mozes M, Bogowsky H, Anteby E et al. (1965). Thrombo-embolic phenomena after
ovarian stimulation with human menopausal gonadotrophins. Lancet 2:1213À5.
Nappi RG, Di Nero E, D™Aries AP & Nappi I. (1998). Natural pregnancy in hypothyroid
woman complicated by spontaneous ovarian hyperstimulation syndrome. Am J
Obstet Gynecol 178:610À11.
Navot D, Bergh PA & Laufer N (1992). Ovarian hyperstimulation syndrome in novel
reproductive technologies: prevention and treatment. Fertil Steril 58:249À61.
Olatunbosun OA, Gilliland B, Brydon LA et al. (1996). Spontaneous ovarian hyper-
stimulation syndrome in four consecutive pregnancies. Clin Exp Obstet Gynecol
23:127À32.
Rabau E, Serr DM, David A et al. (1967). Human menopausal gonadotrophin for
anovulation and sterility. Am J Obstet Gynecol 98:92À8.
Rizk B. (1993). Ovarian hyperstimulation syndrome. In (Studd J, Ed.), Progress in
Obstetrics and Gynecology, Volume 11. Edinburgh: Churchill Livingstone, Chapter 18,
pp. 311À49.
Rizk B & Aboulghar MA (1999). Classi¬cation, pathophysiology and management of
ovarian hyperstimulation syndrome. In (Brinsden P, Ed.), A Textbook of In-Vitro
Fertilization and Assisted Reproduction, Second Edition, Carnforth, UK: Parthenon,
Chapter 9, pp. 131À55.
Schenker JG & Weinstein D (1978). Ovarian hyperstimulation syndrome: a current survey.
Fertil Steril 30:255À68.
Smits G, Olatunbosun O, Delbaere A et al. (2003). Ovarian hyperstimulation syndrome due
to a mutation in the follicle-stimulating hormone receptor. N Eng J Med 349:760À6.
Vasseur C, Rodien P, Beau I et al. (2003). A chorionic gonadotrophin-sensitive mutation
in the follicle-stimulating hormone receptor as a cause of familial gestational
spontaneous ovarian hyperstimulation syndrome. N Engl J Med 349:753À9.
Zalel Y, Orvieto RM, Ben-Rafael Z et al. (1995). Recurrent spontaneous ovarian
hyperstimulation syndrome associated with polycystic ovary syndrome. Gynecol
Endocrinol 9:313À15.
II

EPIDEMIOLOGY OF OVARIAN
HYPERSTIMULATION SYNDROME:
IATROGENIC AND SPONTANEOUS

Rizk and Smitz (1992), in an analytical study of the factors that in¬‚uence the
incidence of OHSS, found wide variation between different centers. This is
partly because of different de¬nitions for the grades of severity and partly
because of the adoption of different criteria for prevention. The incidence of
OHSS has been estimated at 20À33% for mild cases, moderate cases of OHSS
are estimated at 3À6%, and severe cases at 0.1À2% (Rizk, 1993a, b; Serour

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