Case Western Reserve University, Department of Reproductive Biology, University Hospitals of Cleveland, Department of Obstetrics and Gynecology, Cleveland, Ohio, USA
Dear Sir,
It was with great interest that I read the papers by Friedler et al. (1998) and Wood et al. (1998) recently published in your journal. In these papers, a total of three cases of right-sided pleural effusion were described in association with the ovarian hyperstimulation syndrome (OHSS). I would like to share a few remarks on the possible aetiology of such findings. Pleural effusion in association with OHSS is indeed a rare complication of ovulation induction. A recent Canadian study where 771 patients were treated with menotrophins revealed that severe OHSS occurred in 22 patients (3%), pleural effusions occurred in five (0.65%), and only one required a thoracentesis (0.12%) (Levin et al., 1995). The exact pathogenesis of OHSS remains a mystery. This syndrome could be precipitated by an ovarian product, vasoactive peptide or cytokine that has been released into the peritoneal cavity by the ovary, or that has gained access to the systemic circulation directly from the corpus luteum and/or serosal vessels (Loret de Mola et al., 1996
). Specifically, interleukin-6 (IL-6) has been shown to be markedly elevated in the follicular fluid and ascites, as well as serum and pleural effusions from patients with severe OHSS (Loret de Mola et al., 1996
, 1997
).
The pathophysiology of massive hydrothorax concurrently with minimal ascites has been described previously (Loret de Mola et al., 1997). It has been proposed that the diaphragmatic lymphatics are a route for the transfer of ascites into the pleural space in cases of cirrhosis and Meigs syndrome. Others suggest that the ascites pass through diaphragmatic anatomical defects entering the pleural space. Multiple macroscopic defects covered only with thin membranes have been directly observed in the tendinous portion of the diaphragm by laparoscopy, open thoracotomy, and postmortem (Johnson and Loo, 1964
). There are several documented cases of massive pleural effusion among patients undergoing peritoneal dialysis, where the composition of the effusion is mainly peritoneal dialysate (Grefberg et al., 1983
). Exposure to the high pressure of ascites transforms these attenuated areas into blebs, which protrude into the thorax. When these blebs rupture, the negative intrathoracic pressure preferentially allows for the ascites to permeate through these open channels. These defects are more common on the right diaphragm, which explains the almost exclusive predominance of right-sided effusions described by the authors and others. Reports have also linked a higher rate of such defects among women. The evidence of Methylene Blue passing from the abdominal to pleural cavities when injected is compatible with both these hypotheses. Upon careful examination, abdominal ultrasound usually reveals mild to moderate ascites in these patients, which is sometimes more evident when the patient changes position or sides during the examination. Conversely, small unilateral or bilateral pleural effusions can also be observed in many patients with moderate and severe forms of OHSS without pulmonary compromise. It would be rather unlikely that a systemic peptide will target its vascular permeability effects on the pleural space unilaterally, without affecting any other serosal membrane. Furthermore, pleural fluid IL-6 levels are comparable to values reported in ascites, which are 100 times higher than normal serum, also supporting a passive movement from the abdomen into the pleural space (Loret de Mola et al., 1997
). The normal drainage of the diaphragmatic lymphatics would explain the nature of pleural effusions in cases of chronic ascites such as cirrhosis, whereas anatomical defects provide a more adequate explanation to the acute hydrothorax associated with peritoneal dialysis and OHSS.
Given the complications associated with the syndrome, I agree with the authors that women presenting with a history of dyspnea following the use of exogenous gonadotrophins or fertility medications should have an imaging assessment of the chest in order to diagnose pulmonary compromise, so that patients can be treated accordingly.
References
Friedler, S., Rachstein, A., Bukovsky, I. et al. (1998) Unilateral hydrothorax as a sole and recurrent manifestation of ovarian hyperstimulation syndrome following in-vitro fertilization. Hum. Reprod., 13, 859861.[Abstract]
Grefberg, N., Danielson, B.G., Benson, L. and Pitkanen, P. (1983) Right-sided hydrothorax complicating peritoneal dialysis. Nephron, 34, 130134.[ISI][Medline]
Johnson, R.F. and Loo, R.V. (1964) Hepatic hydrothorax: studies to determine the source of the fluid and report of thirteen cases. Ann. Intern. Med., 61, 385.[ISI]
Levin, M.F., Kaplan, B.R. and Hutton, L.C. (1995) Thoracic manifestations of ovarian hyperstimulation syndrome. Can. Assoc. Rad. J., 46, 2326.
Loret de Mola, J.R., Flores, J.P., Baumgardner, G. et al. (1996) Elevated interleukin-6 levels in the ovarian hyperstimulation syndrome: ovarian immunohistochemical localization of interleukin-6 signal. Obstet. Gynecol., 87, 581587.
Loret de Mola, J.R., Arredondo-Soberon, F., Randle, C.P. et al. (1997) Markedly elevated cytokines in pleural effusion during the ovarian hyperstimulation syndrome: transudate or ascites?. Fertil. Steril., 67, 780782.[ISI][Medline]
Wood, N., Edozien, L. and Lieberman, B. (1998) Symptomatic unilateral pleural effusion as a presentation of ovarian hyperstimulation syndrome. Hum. Reprod., 13, 571572.[Abstract]
IVF and Infertility Unit, Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin, 70300 Israel
Dear Sir,
We thank Dr Loret De Mola for his interest in our report (Friedler et al., 1998) and his comments concerning the possible pathophysiology of unilateral pleural effusion in ovarian hyperstimulation syndrome (OHSS). The explanation he offers involving defects in the tendinous portion of the diaphragm, more prevalent in women and on the right side, which allows, under the suctioning effect of negative intrathoracic pressure, accumulation of ascitic fluid in the thorax, seems to be a logical proposition. I agree that the likelihood of a localized effect, targeted at unilateral vascular permeability on pleural serosa only, of a systemic peptide is quite low. Until direct proof is available concerning the exact pathophysiology of this disturbing manifestation of OHSS, I am happy to acknowledge that we all agree upon the need to raise awareness to the possibility of thoracic involvement of OHSS, that is fairly easy to diagnose and imperative to treat.
References
Shevach, F., Rachstein, A., Bukovsky, I. et al. (1998) Unilateral hydrothorax as a sole and recurrent manifestation of ovarian hyperstimulation syndrome following in-vitro fertilization. Hum. Reprod., 13, 859861.[Abstract]