LINEBURG


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1989; Friedler et al., 1998; Gore et al., 2002). It has been suggested that
the diaphragmatic lymphatics are a route for the transfer of ascites into the
pleural space in cases of cirrhosis and Meig™s syndrome. Multiple macroscopic
defects covered only with thin membranes have been directly observed in
the tendinous portion of the diaphragm by laparoscopy and open thoracotomy.
104
Table V.4 Isolated pleural effusion as the only manifestation of OHSS
Reproduced with permission from Gore et al. (2002). Middle East Fertility Society Journal 7:211À13

Author and Jewelewicz
year of and Van de Kingsland Daniel Bassil et al., Wood et al., Friedler et al., Friedler et al., Man et al., Arikan Gore et al.,
publication Wide, 1975 et al., 1989 et al., 1995 1996 1998 1998 (case 1) 1998 (case 2) 1997 (4 cases) et al., 1997 2002

Age 24 35 27 39 29 29 33 24À29 29 27
Peak follicular 180 mg/ 1221 nmol/ 1900 ng/ml 2650 pg/ml 3479 pg/ml 43000 pg/ml 43000 pg/ml NM* NM* 1840 pg/ml
E2 level 24 h 24 h
No. of oocytes none 7 none 11 18 22 19 NM* NM* none (IUI)**
retrieved
Luteal support none none none progesterone hCG progesterone progesterone NM* NM* hcG and
progesterone
Onset of OHSS 13 days 10 days 10 days 12 days 6 days 12 days 5 days NM* 12 days 10 days
hCG after hCG after oocyte after hCG after oocyte after oocyte after oocyte after oocyte after oocyte after hCG
administration retrieval administration retrieval retrieval retrieval retrieval retrieval administration
Hydrothorax right side right side right side left side right side right side right Side right side left side right side
(recurrent) (one left sided) (recurrent)
Fluid drained none (resolved 3.5 l 2l 2.5 l 4l 1.7 l 4.5 l 1.2 lÀ2 l 4l 10.4 l
spontaneously)
Presence of none none none none none minimal none none minimal none
ascites
Conception in vivo IVF-ET in vivo IVF-ET none IVF-ET none IVF-ET in IVF-ET in vivo
followed by (twins) (after (twins) (after one case (NM* (twins)
miscarriage IVF-ET) IVF-ET) for other cases)

* NM ¼ not mentioned
** IUI ¼ intrauterine insemination
105
RESPIRATORY COMPLICATIONS




There are documented cases of massive pleural effusion in patients who are
undergoing peritoneal dialysis. Loret de Mola (1999) suggested that exposure to
high pressure of ascites transforms these attenuated areas into blebs, which
protrude into the thorax. The negative intrathoracic preferentially allows for
the ascites to permeate through the open channels when the blebs rupture.
These defects are more common on the right diaphragm, which explain the
predominance of cases of right-sided pleural effusion reported in the literature
(Gore et al., 2002).


Is the Pleural Effusion Transudate or Exudate?
Chemical analysis of the ¬‚uid obtained from pleurocentesis revealed both
transudates (Daniel et al., 1995; Bassil et al., 1996; Friedler et al., 1998; Wood
et al., 1998; Rabinerson et al., 2000) and exudates (Kingsland et al., 1989; Man
et al., 1997; Gregory and Patton, 1999; Roden et al., 2000). This observation
remains unexplained, as this may re¬‚ect the possibility of multiple mechanisms
involved in the pathogenesis of isolated hydrothorax.


Adult Respiratory Distress Syndrome
Adult respiratory distress syndrome (ARDS) is de¬ned as severe hypoxemia
of acute clinical onset and bilateral scattered pulmonary in¬ltrates on a frontal
chest radiograph (alveolar in¬ltrate) after exclusion of left atrial or pulmonary
capillary hypertension (Delvigne and Rozenberg, 2003). Zosmer et al. (1987)
reported the ¬rst case of ARDS complicating ovulation induction. The
authors considered pulmonary capillary leakage induced by prostaglandin
release, hypoalbuminemia and shift of dextran-40 molecules to the intralveolar
space to be the most probable reason for the occurrence of this complication.
Abramov et al. (1999a), in a series of cases of pulmonary complications
following OHSS, noted that ARDS occurred after pronounced hydration.
In their series, one patient with ARDS had dyspnea and 80% had a temper-
ature of over 38 degrees. On auscultation, the patients had bilateral
decrease of respiratory sounds in addition to the presence of bilateral pul-
monary rauls.
Prostaglandins and cytokines may play a role in the pathophysiology
of ARDS. The increase in vascular permeability results in a leakage of plasma
and colloids resulting in pulmonary edema and atelectasis, which would be
fatal. Schenker and Ezra (1994) reported 50% recovery without sequelae.


Renal Complications
Prerenal failure is a complication of hypovolemia secondary to ¬‚uid
transudation in the peritoneal cavity. Balasch et al. (1990) reported a case of
prerenal failure after treatment with indomethacin and advised against the use
of prostaglandin synthetase inhibitors. Ovarian hyperstimulation syndrome
in a renal transplant patient undergoing assisted conception treatment was
106 COMPLICATIONS OF OVARIAN HYPERSTIMULATION SYNDROME




reported (Khalaf et al., 2000). Ovarian enlargement secondary to OHSS resulted
in obstruction in the transplanted kidney and deterioration of renal function.
Conservative management was successful and a live twin birth was later
achieved by replacement of two frozenÀthawed embryos.


Liver Dysfunction
Abnormal liver functions tests occur in 25À40% of cases (Forman et al., 1990;
Delvigne and Rozenberg, 2003; Fabregues et al., 1999). Sueldo et al. (1988) and
Younis et al. (1988) were the ¬rst to report liver dysfunction in severe OHSS.
Since then, abnormal hepatic function has been increasingly recognized as
a complication of severe OHSS that may persist for over two months. It
was interesting to note that, although the liver function tests were markedly
abnormal, liver biopsy showed signi¬cant morphological abnormalities only
at the ultrastructural level.


ETIOPATHOLOGY OF LIVER ABNORMALITIES IN OHSS

The relationship of serum pro-in¬‚ammatory cytokines and vascular endothelial
growth factor with liver dysfunction in severe OHSS was studied (Rizk, 1993b;
Southgate et al., 1999; Chen et al., 2000). Concentrations of IL-6 in the active
phase of OHSS were signi¬cantly higher in the abnormal liver function tests
group than in the normal liver function tests group. These results suggest that
the IL-6 cytokine system may play a role in pathogenesis of liver dysfunction
in severe OHSS. Abnormal liver function tests were associated with lower
clinical pregnancy rates.
Elter et al. (2001) reported a case of hepatic dysfunction associated with
moderate OHSS, suggesting that hepatic dysfunction is not limited to severe
forms of OHSS. Liver function should be analyzed even in moderate cases.
Davis et al. (2002) reported a severe case of OHSS with liver dysfunction
and malnutrition, in which the patient™s albumin dropped to 9 g/l associated
with liver function abnormalities: alanine aminotransferase 46 IU/l, alkaline
phosphatase 706 IU/l, bilirubin 26 mmol/l and prothrombin time 19 s. The
judicious use of paracentesis and commencement of total parenteral nutrition
coincided with a rapid clinical improvement. One month after discharge,
the patient was asymptomatic with normal liver function.


RECURRENT CHOLESTASIS

Recurrent cholestasis is unique to pregnancy and typically manifests during
the last trimester. Characteristically, the ¬rst symptom is pruritus which
is associated with serum bile acids and abnormal liver functions. The disease
usually resolves spontaneously within a few days after delivery. A case of
recurrent cholestasis during a twin pregnancy following IVF has been reported
107
RECURRENT CHOLESTASIS




(Midgley et al., 1999). It was proposed that the patient had a genetic
predisposition to developing cholestasis on separate occasions, initially in the
¬rst trimester secondary to abnormally high estrogen concentration following
OHSS and subsequently in the third trimester as is typical of obstetric
cholestasis.


Gastrointestinal Complications
With the widespread use of ovulation induction for assisted conception, it is
mandatory that general practitioners become aware that gastrointestinal
symptoms may be the initial presentation of ovarian hyperstimulation (Rizk
and Aboulghar, 1991, 2005). One such case presented to us with a cerebro-
vascular accident because such symptoms were ignored (Rizk et al., 1990).


Mesenteric Artery Occlusion in OHSS
Mesenteric resection after massive arterial infarction has been reported
(Aurousseau et al., 1995).


Duodenal Ulcer Perforation
Uhler et al. (2001) reported the ¬rst case of perforated ulcer following severe
OHSS. A 29-year-old nulligravid woman with polycystic ovarian syndrome
underwent her ¬rst attempt at IVF in Chicago. A long protocol luteal
phase GnRH agonist was used for pituitaryÀovarian axis down-regulation
followed by FSH for ovarian stimulation. On the tenth day of FSH
administration, more than 10 follicles measured at least 18 mm in diameter
on ultrasound, and the estradiol level was 4245 pg/ml on the day of hCG.
Transvaginal ultrasound-guided follicular aspiration yielded 19 oocytes at 36 h
after administration of 5000 IU of hCG. No fresh embryos were transferred and
11 cleaved embryos were cryopreserved. Two days later, the patient complained
of abdominal distension, shortness of breath and mid to upper abdominal
pain, and presented to her physician™s of¬ce for the evaluation of possible
OHSS. She was admitted to the hospital for observation and intravenous
hydration. On hospital day 10, she underwent exploratory laparotomy and
a posterior perforation of the posterior duodenum that required antrectomy
gastrojejeunostomy and lateral tube duodenostomy for the control of the
perforation. The pathology report con¬rmed chronic gastritis and Helicobacter
pylori. The patient required prolonged assisted ventilation, and on hospital
day 22 she required a tracheostomy tube placement, and then she was weaned
to a tracheostomy collar of humidi¬ed air and her nutritional support was via
a feeding tube. The patient was hospitalized for a total of 47 days and then
transferred to a rehabilitation center for an additional 30 days before
being discharged home. The patient had her tracheostomy removed during
her stay at the ¬rst two-week rehabilitation center, and then was transferred
to another rehabilitation center for her last two weeks for intensive physical
108 COMPLICATIONS OF OVARIAN HYPERSTIMULATION SYNDROME




and occupational therapy. She was ¬nally discharged home 86 days after her
IVF cycle. The authors felt that in this critically ill patient with OHSS, severe
stress associated with invasive monitoring and multiple therapies in the
intensive care unit, as well as H. pylori infection, were probably the most likely
causal factors of her perforated duodenum. We are aware of a similar case in
the UK that resulted in mortality following perforated duodenum and other
associated complications from intensive monitoring.


OHSS COMPLICATED PERITONITIS DUE TO
PERFORATED APPENDICITIS

Fujimoto et al. (2002) reported a case of peritonitis due to a perforated
appendix. The patient presented with abdominal distension after ovarian
stimulation with hMG followed by hCG to trigger ovulation. The patient
developed massive ascites and swollen ovaries and was admitted with a
diagnosis of OHSS. An intravenous infusion of serum albumin and low dose
dopamine were administered to increase her ¬‚uid output. The dopamine failed
to increase her urinary output, the abdominal symptoms deteriorated and
paracentesis revealed infected foul-smelling ¬‚uid. An emergency laparotomy
was performed and the ¬nal diagnosis was peritonitis due to perforated
appendix and a right tubal pregnancy. Appendectomy, right salpingectomy and
vigorous irrigation and drainage were performed. The authors caution that
OHSS may not only mask typical manifestations of appendicitis, but could also
compromise concurrent intraperitoneal infection.


BENIGN INTRACRANIAL HYPERTENSION

Lesny et al. (1999) reported a case of OHSS and benign intracranial
hypertension in pregnancy after IVF/ET. Shortly after embryo transfer, the
patient developed clinical signs of moderate OHSS with symptoms which were
later diagnosed as benign intracranial hypertension (BIH). The BIH was treated
effectively using repeated lumbar puncture and diuretics. Spontaneous labor
and delivery occurred at 40 weeks™ gestation. There was no neurological sequel
and no recurrence of the BIH two years after the pregnancy. The possible
link between OHSS and BIH as well as the risks of further pregnancy should
be considered.


Mesothelial Cells Proliferation in Lymph Nodes after Severe OHSS
Endometriosis and endosalpingiosis are the most well known benign
intranodal heterotopic inclusions. Leiomyomatosis, and intranodal inclu-
sions of nevus and decidua are much less common (Colby, 1999). Van der
Weiven et al. (2005) reported a rare case of ectopic mesothelial preformation
in cervical lymph nodes after severe OHSS. They reported a rare case in which
109
OBSTETRIC COMPLICATIONS




a 42-year-old woman underwent successful IVF and developed severe OHSS,
and pathologically enlarged cervical lymph nodes. Familiarity with this event is
important for the clinician, as well as for the pathologist, in order to prevent the
misdiagnosis of malignancy.


FEBRILE MORBIDITY

Febrile morbidity is common during OHSS. Abramov et al. (1998a) performed
the most comprehensive study to de¬ne the incidence of febrile morbidity
and its causes in severe and critical OHSS. The authors reviewed the medical
records of all OHSS patients hospitalized in 16 out of 19 tertiary medical
centers in Israel between January 1987 and December 1996. They de¬ned febrile
morbidity as at least one temperature rise above 38°C, lasting ¸24 h. They
identi¬ed 2902 patients who had 3305 hospitalizations as a result of OHSS,
of whom 196 had severe and 13 critical OHSS. The incidence of febrile
morbidity in these 209 patients was 82.3%. The causes of the infections are
presented in Table V.5. The causative organisms encountered are presented in
Table V.6. Interestingly, no infectious etiology could be found in 50.2% (105
patients). Hypoglobulinemia was observed in most patients. The ascitic and
pleural ¬‚uids aspirated from these patients contained high globulin
concentrations. Abramov et al. (1998a) concluded that infection-related febrile
morbidity in severe and critical OHSS is high and may be related to immune
de¬ciency that resulted from the loss of plasma globulins to the third space
(Abramov et al., 1999b). Interestingly, non-infection-related febrile morbidity
was possibly related to endogenous pyrogenic mechanisms (Abramov et al.,
1998a).


OBSTETRIC COMPLICATIONS
Early Pregnancy Complications
Raziel et al. (2002) reported increased early pregnancy loss in IVF patients
with severe OHSS (38% as compared to 15% in the control group). Abnormal
hCG levels may occur in early pregnancy in patients with ovarian hyper-
stimulation syndrome. However, these abnormal levels do not predict poor
outcome in pregnancies complicated by OHSS (Samuel and Grosskinsky,
2004); therefore, they are not helpful in the decision-making process to
diagnose ectopic pregnancy or otherwise compromised pregnancies.


Late Pregnancy Complications
A higher prevalence of obstetric complications have been reported in
pregnancies following IVF, mainly as a result of multiple pregnancy, but
also independent of multiplicity (Rizk et al., 1991b; Tan et al., 1992).
Selection of appropriate control groups is of paramount importance in
110 COMPLICATIONS OF OVARIAN HYPERSTIMULATION SYNDROME




Table V.5 Febrile morbidity in patients with severe and critical
OHSS
Reproduced with permission from Abramov et al. (1998a). Hum
Reprod 13:3128À31

No. of
patients (%)

2.3 + 0.8
Mean (+SD) febrile episodes/patient
34.6 + 8.2
Mean (+SD) duration of febrile episodes (documented infections)
UTI
positive 35 (16.7)
probable 8 (3.8)
Pneumonia
positive 4 (1.9)
probable 4 (1.9)
URTI
positive 3 (1.4)
probable 4 (1.9)
Intravenous line phlebitis
positive 2 (1.0)
probable 2 (1.0)
Cellulitis at an abdominal puncture sight
positive 2 (1.0)
probable 0 (0.0)
Gluteal abscess at the site of progesterone injection
positive 1 (0.5)
probable 0 (0.0
Postoperative wound infection 2 (1.0)
Peritonitis 0 (0.0)
Total infection rate 67 (32.1)
Antibiotic treatment
Intravenous 9 (4.3)
Oral 58 (27.8)
5.2 + 2.1
Mean (+SD) duration of treatment (days)
No. of documented infections 105 (50.2)
Total febrile morbidity 172 (82.3)



determining whether IVF pregnancies have a higher or lower rate of perinatal
complications (Brinsden and Rizk, 1992; Rizk et al., 1991c). Only a few studies
examined the pregnancy outcome speci¬cally in IVF patients who developed
OHSS (Abramov et al., 1998b; Mathur and Jenkins, 2000). In the larger
111
OBSTETRIC COMPLICATIONS




Table V.6 Infective organisms isolated from
patients with severe OHSS
Reproduced with permission from Abramov et al.
(1998). Hum Reprod 13:3128À31

No. of
Infection/organism patients (%)

UTI*
Proteus mirabilis 12 (34.3)
Klebsiella pneumoniae 7 (20.0)
Pseudomonas aeruginosa 6 (17.1)
Escherichia coli 4 (11.4)
Morganella morganii 2 (5.7)
Proteus vulgaris 2 (5.7)
Staphylococcus aureus 1 (2.9)
Enterobacter cloacae 1 (2.9)
Pneumonia
Pseudomonas aeruginosa 1 (25.0)
Klebsiella pneumoniae 1 (25.0)
Staphylococcus aureus 1 (25.0)
Streptococcus pneumoniae 1 (25.0)
URTI**
Group A streptococcus 1 (33.3)
M/P viral 2 (66.7)
Intravenous line phlebitis
Staphylococcus epidermidis 1 (50.0)
Pseudomonas aeruginosa 1 (50.0)
Cellulitis at an abdominal puncture site
Staphylococcus aureus 1 (100)
Postoperative wound infection
Staphylococcus aureus 1 (50)
Pseudomonas aeruginosa 1 (50)

* UTI ¼ urinary tract infection
** URTI ¼ upper respiratory tract infection




study by Abramov et al. (1998b), the control group was selected from
international data, whereas in the smaller study by Mathur and Jenkins (2000)
a contemporaneous control group was used. Abramov et al. (1998b) reported
that, among IVF patients with severe and critical OHSS, pregnancy rates,
multiple gestations, miscarriage, preterm premature rupture of the membranes,
112 COMPLICATIONS OF OVARIAN HYPERSTIMULATION SYNDROME




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