Pleural Disease in Obstetrics and Gynecology
In this chapter, the pleural effusions seen in the practice of obstetrics and gynecology are discussed. The ovarian hyperstimulation syndrome (OHSS) occurring before pregnancy, fetal pleural effusions, postpartum pleural effusion, Meigs’ syndrome, and finally, the pleural effusions secondary to endometriosis are addressed.
OVARIAN HYPERSTIMULATION SYNDROME
OHSS is a serious complication of ovulation induction with human chorionic gonadotropin (hCG) and occasionally clomiphene (1). This syndrome is characterized by ovarian enlargement, ascites, pleural effusion, hypovolemia, hemoconcentration, and oliguria (2). A rare complication is the occurrence of thromboembolism related to hemoconcentration (2). The severe form with ascites or pleural effusion, or both, occurs in approximately 3% of patients undergoing ovulation induction for in vitro fertilization, but radiologically evident pleural effusions develop only in approximately 1% (3).
Pathogenesis
OHSS has two primary components: (a) enlargement of the ovaries accompanied by the formation of follicular, luteal, and hemorrhagic ovarian cysts and edema of the stroma, and (b) an acute shift of fluid out of the intravascular space (3). The syndrome is more frequent in cycles resulting in pregnancy (4). The exact pathogenesis of this syndrome is not clear. At one time, it was thought that the OHSS resulted from high local concentrations of estrogen in the ovaries causing altered capillary permeability and ascites, which, in turn, led to the pleural effusion. This does not appear to be the sole explanation, however, because the syndrome can still be produced in rabbits when the ovaries are exteriorized (5). This indicates that there must be systemic effects involved in the fluid shifts into the peritoneal and pleural cavities. It is now believed that the syndrome is 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 or serosal vessels. Three likely candidates are vascular endothelial growth factor (VEGF) (6,7), interleukin 8 (IL-8) (7), and interleukin 6 (IL-6) (6). All three have been shown to be markedly elevated in the follicular fluid and ascites. Antibodies to VEGF reduce the ascitesinduced endothelial permeability to 44% of control and antibodies to IL-8 reduce the ascites-induced endothelial permeability to 34% of control (7). Antibodies to IL-6 do not significantly affect ascitesinduced endothelial permeability (7). It has also been shown that hCG upregulates the VEGF expression of granulosa cells in the OHSS, but not in control groups (8). The serum levels of VEGF are elevated in patients with OHSS (8). The mean levels of VEGF in ascitic fluid with the OHSS (7) are higher than the mean level of VEGF in any type of pleural effusion (7). The mean level of VEGF in the pleural fluid with the OHSS is elevated but is only about 60% that in ascitic fluid (9).
There are probably two factors responsible for the accumulation of pleural fluid with OHSS. In patients with bilateral effusions, the probable mechanism is a generalized capillary leak syndrome. In patients with large right-sided pleural effusions, it is probable that the fluid moves directly from the peritoneal space to the
pleural space. Evidence supporting this mechanism is the fact that the effusions are frequently large and rightsided, many patients have ascites, and the observation in one patient that the pleural fluid IL-6 level was more than 100 times higher than the simultaneously obtained serum level (10). Obviously, the pleural fluid in this case was not due to a generalized capillary leak syndrome.
pleural space. Evidence supporting this mechanism is the fact that the effusions are frequently large and rightsided, many patients have ascites, and the observation in one patient that the pleural fluid IL-6 level was more than 100 times higher than the simultaneously obtained serum level (10). Obviously, the pleural fluid in this case was not due to a generalized capillary leak syndrome.
Clinical Manifestations
Patients with OHSS initially develop abdominal discomfort and distension, followed by nausea, vomiting, and diarrhea. As the syndrome worsens, the patients develop evidence of ascites and then hydrothorax or breathing difficulties. In the most severe stages, the patients develop increased blood viscosity due to hemoconcentration, coagulation abnormalities, and diminishing renal function (3). Respiratory symptoms develop 7 to 14 days after the hCG injection (4).
The pleural effusions with OHSS are usually right sided. In the series of 33 patients with pleural effusions reported by Abramov et al. (11), 17 effusions (52%) were right sided, 9 (27%) were bilateral, and 7 (21%) were unilateral left sided. At times, a pleural effusion may be the sole manifestation of OHSS (12). The pleural effusion can be a significant problem, as evidenced by one patient who had 8,500 mL pleural fluid aspirated from her pleural space over 14 days (13). The pleural fluid in patients with OHSS is an exudate. In the series of Abramov et al. (14), the mean pleural fluid protein was 4.1 g/dL, whereas the mean serum protein was 4.4 g/dL.
The incidence of the syndrome can be reduced if the serum estrogen levels and the number of ovarian follicles are monitored. If the serum estrogen levels are very high or if there are more than 15 ovarian follicles with a high proportion of small and intermediate size follicles, hCG should be withheld (2).
Treatment
The treatment of the OHSS is primarily supportive (1). Hemoconcentration should be treated with intravenous fluids, because hypovolemia can lead to renal failure and even death. If the patient has a large pleural effusion and is dyspneic, a therapeutic thoracentesis should be performed. Rarely is more than one therapeutic thoracentesis necessary (1).
FETAL PLEURAL EFFUSION
The ability to diagnose fetal abnormalities prenatally has been facilitated by diagnostic ultrasound. One abnormality now diagnosed on occasion is fetal pleural effusion. Almost all neonatal pleural effusions are probably persistent fetal pleural effusions. The prevalence of fetal pleural effusion is approximately 1 in 10,000 deliveries (15). The prevalence is approximately twice as high in boys as in girls (16). There is one report of a patient who had three children, each of whom had a fetal pleural effusion (17).
Very early in pregnancy, the incidence of pleural effusion is higher. In one study of 965 pregnancies evaluated by ultrasound between 7 and 10 weeks, the incidence of pleural effusion was 1.2% (18). These early pregnancies complicated by effusion had poor outcomes with miscarriages in 86% (18).
If the fetal pleural effusion is untreated, there is a high mortality rate. In one series of untreated patients, the mortality rate was 37% for 54 untreated fetuses (15). The high perinatal mortality rate in cases of fetal pleural effusion is related to three factors: development of nonimmune hydrops, prematurity, and pulmonary hypoplasia (15). Intrathoracic compression of the developing lung produces pulmonary hypoplasia. This pulmonary hypoplasia can sometimes result in perinatal death. The mortality rate is also higher if there are associated chromosomal abnormalities or structural abnormalities. Ruano et al. (19) reported that the mortality of fetuses with isolated pleural effusions was 5 of 14 (36%), of those with structural abnormalities and no chromosomal abnormalities 19 of 19 (100%), of those with chromosomal abnormalities 20 of 23 (87%). The most common chromosomal abnormality in the series of Ruano et al. (19) was Turner syndrome, which occurred in 15 of the 23 patients (65%).
Pathogenesis and Clinical Manifestations
The pathogenesis of fetal pleural effusion is not known and is possibly multifactorial. There is some evidence that the fetal pleural effusions are actually chylothoraces. Benacerraf and Frigoletto (20,21) analyzed the pleural fluid from two fetuses and reported abundant lymphocytes in both, but one had almost all T lymphocytes, whereas the other had a mixture of T and B lymphocytes. The presence of the lymphocytes was suggestive of a chylous effusion. A ratio of the pleural fluid to serum IgG that exceeds 0.6 is very suggestive of a neonatal pleural effusion (22). In addition, most neonatal pleural effusions, which in many cases are continuations of fetal pleural effusions, are chylothoraces (23). Analysis of the pleural fluid for chylomicrons is not useful in the diagnosis of fetal chylothorax because the fetuses are not eating any lipids.
In a review of the literature for isolated fetal pleural effusion in 1998, 204 cases were found (24). The fetal pleural effusions were bilateral in 74%, unilateral right sided in 11%, and unilateral left sided in 14% (24). Polyhydramnios was noted in 72% and hydrops fetalis in 57% (24). The reason for the polyhydramnios is not clear, but it has been suggested that the increased intrathoracic pressure may interfere with normal fetal swallowing. There is a high frequency of chromosomal abnormalities in fetuses with pleural effusions. In one series, the prevalence of chromosomal abnormalities was 50% in 152 fetuses with other sonographic abnormalities and 12% in 94 patients with isolated pleural effusion (25).
Treatment
The optimal management for fetuses with pleural effusions is controversial (15). If the pleural effusions are not treated, some resolve spontaneously whereas others deteriorate to generalized hydrops. In one review of 204 cases, spontaneous remission occurred in 22% (24). Characteristics of cases that resolved spontaneously included diagnosis made early in the second trimester, unilateral effusion, and no associated polyhydramnios or hydrops (24). Some infants die from pulmonary hypoplasia after delivery, whereas others survive. In a review of 82 cases in 1993, the mortality rates of those treated surgically and those treated conservatively were comparable (15). Overall, the mortality rate in cases not terminated by abortion was 36% (15). However, in a second review in 1998, 43% of the fetuses with treatment had a good outcome whereas only 22% without treatment had a favorable outcome (24). In a more recent review (26) of 172 fetuses with isolated pleural effusion, the overall survival rate was 63% with various treatment approaches.
The following scheme is suggested for the management of fetal pleural effusion. When a pleural effusion is discovered in a fetus, a thoracentesis is performed immediately if there is fetal distress or if there is diaphragmatic inversion or shift of the mediastinum to the contralateral side (27). Otherwise the fetus is evaluated for other abnormalities. Then a repeat ultrasound is obtained in 2 to 3 weeks. If the effusion has decreased in size, then the fetus is followed with scans every 2 to 3 weeks. If the effusion is stable, then serial scans are performed and a thoracentesis is performed immediately before delivery to facilitate neonatal resuscitation. If the effusion increases in size, then a diagnostic amniocentesis should be performed for chromosomal analysis and culture of amniotic fluid to screen for bacterial or viral infection. At the same time, a diagnostic thoracentesis should be performed and the pleural fluid sent for culture, cell analysis, and biochemical study. The lung size and the fetal lung distensibility are assessed through ultrasound before and after the thoracentesis. Fetuses that have less-than-normal lung expansion are then subjected to surgical intervention.
The possible surgical interventions for fetal pleural effusion are pleuroamniotic shunt or repeated therapeutic thoracentesis. Rodeck et al. (28) reported their results with the implantation of pleuroamniotic shunts in eight human fetuses with pleural effusion. These shunts were established with double-pigtail nylon catheters with external and internal diameters of 0.21 and 0.15 mm, respectively. The shunts were introduced transamniotically under ultrasound visualization through the fetal midthoracic wall into the effusion. All eight fetuses in this series had large pleural effusions with hydramnios. Twelve pleuroamniotic shunts were placed in these fetuses. One shunt was noted to be free in the amniotic cavity 1 week after insertion and a second shunt was inserted. The remaining 11 shunts functioned until delivery (median 2.5 weeks; range 1-14 weeks). In six fetuses, the pleural effusions almost completely resolved and the hydramnios disappeared. Three of the six fetuses had hydrops that resolved after the insertion of the shunt. All six infants survived, and five had no respiratory difficulty at birth. Fetal hydrothoraces did not resolve in two patients, both of whom had hydrops and died shortly after delivery. In a second study, Blott et al. (29) inserted shunts into 11 fetuses between 24 and 35 weeks of gestation and reported that the effusions were successfully drained in all cases and that 8 of the 11 fetuses survived. It should be noted that the shunts become displaced intrathoracically in a sizeable percentage of fetuses, but there appears to be no long-term pulmonary complications and they do not need to be removed (30).