Antenatal treatment of chylothorax and cystic hygroma with OK-432 in nonimmune hydrops fetalis

OBJECTIVES: To present our experience of using OK-432 in treating fetal cystic hygroma and chylothorax complicated with nonimmune hydrops fetalis. METHODS: OK-432 (Picibanil) was injected into the fetal pleural cavity or fetal cystic hygroma. RESULTS: Patient 1: A 23-year-old, gravida 2, para 1, was found to have a recurrent fetal chylothorax at GA 29 weeks. Serial amnioreduction and thoracocentesis was performed at GA 31, 32, 33, and 34 weeks. Intrapleural OK-432 injection was performed twice at GA 33 and 34 weeks. Cyanosis and respiratory distress were noted immediately after birth (GA 34 weeks). The baby expired despite of aggressive neonatal resuscitation. Patient 2: A 26-year-old, gravida 2, para 1, was found to have a cystic hygroma of her fetus at GA 17 weeks. Karyotype of the cystic fluid and the amniocytes were 46, XY. Fetal ascites developed at GA 22 weeks. OK-432 injection into the tumour was performed at GA 23 weeks. Stabilization of the cystic hygroma was noted throughout the pregnancy (about 3.5 cm in diameter). Serial fetal paracentesis and/or amnioreduction were performed. Karyotype of the ascites was again 46, XY. Maternal dietary modification with medium chain triglyceride was also prescribed. Chylothorax developed and the baby was born by cesareans at GA 32 weeks. Resolution of pleural effusion, ascites, and regression of cystic hygroma were noted since the 2nd day after birth. The baby had survived beyond 4 months of age at submission. CONCLUSION: Combination of antenatal OK-432 injection, maternal dietary modification, serial thoracocentesis plus paracentesis, together with amnioreduction and tocolysis, appeared to contribute to the success of antenatal treatment. Fetal pulmonary expansion may determine the immediate neonatal survival.     

New treatment of early fetal chylothorax

OBJECTIVE: To evaluate OK-432, a preparation of Streptococcus pyogenes, in the treatment of early fetal chylothorax. METHODS: A prospective study of all fetuses (n=7) with persistent early chylothorax (gestational ages 16-21 weeks) referred to the tertiary center of fetal medicine in Denmark in 2003-2005. Fetuses were injected with 0.2-1.0 mg of OK-432 into the pleural cavity. The treatment was repeated if there were persistent or increasing pleural effusions after 1-3 weeks. The main outcome measures included remission of pleural effusions and fetal and infant morbidity and mortality. RESULTS: Total remission of pleural effusions was obtained in all fetuses after one or two intrapleural injections of OK-432. No adverse effects of the treatment were observed. No fetus developed hydrops, and all experienced an uncomplicated third trimester. All children were born healthy without pleural effusions, lung hypoplasia, or hydrops. CONCLUSION: Persistent early chylothorax is a condition with a high mortality rate and no established treatment option. Use of OK-432 is a promising therapy for selected fetuses with persistent chylothorax early in the second trimester.     

Thoracoamniotic shunting with double-basket catheters for fetal chylothorax in the second trimester

The progress of a fetal severe pleural effusion at mid-trimester is extremely poor. We encountered a fetus that developed a severe left pleural effusion at 21 weeks of gestation. The pleural effusion was removed by thoracocentesis at 22 weeks. Cytology revealed abundant lymphocytes, suggesting chylothorax. However, a reaccumulation of pleural effusion with hydrops was subsequently noted, and a thoracoamniotic shunt with double-basket catheters was installed at 23 weeks. The pleural effusion decreased after 24 weeks and completely disappeared at 26 weeks. At 40 weeks of gestation, a female infant was born by vaginal delivery, with no evidence of pleural effusion. We would like to stress that thoracoamniotic shunt with double-basket catheters in the second trimester is effective for pleural effusion with hydrops.     

Successful intrauterine treatment of cystic hygroma colli using OK-432. A case report

A 36-year-old multiparous woman was referred at 25 weeks of gestation with suspected cystic hygroma. Ultrasonographic examination demonstrated large multiple cysts around the fetal neck. We treated them by injection of OK-432 at 29 and 32 weeks of gestation. The cysts decreased in size after the intrauterine treatment. A female baby was delivered at 38 weeks of gestation. She was healthy, and there was only a small swelling of the skin in the nuchal area at birth. One month later, the slight swelling of the skin had completely disappeared. Intrauterine injection of OK-432 was a safe and effective therapy for fetal cystic hygroma.     

Fetal chylothorax response to maternal dietary treatment

Background: Fetal chylothorax is associated with elevated perinatal mortality. Development of mediastinal shift with significant lung compression before 35 weeks’ gestation needs treatment.Case: A 24-year-old gravida 2, para 0 presented at 26 weeks’ gestation with a fetal pleural effusion with a mediastinal shift and abnormal Doppler velocimetry indices in several vessels. Thoracentesis was successful but 3 days later, the fetal effusion had reaccumulated. Because of fetal position, a pleuro-amniotic shunt was difficult technically, so maternal medical treatment was initiated with a low-fat, high medium-chain triglyceride diet. After initial mild decrease, the estimated volume of the fetal chylothorax remained stable until 36 weeks’ gestation, at which time we delivered by cesarean an infant with good Apgar scores. After aspiration of the remaining thoracic fluid and administration of a similar diet, the infant did well, with normal growth and development.Conclusion: Maternal dietary treatment might help delay the need for thoracentesis in cases of fetal chylothorax.     

A case of intrauterine medical treatment for cystic hygroma

We report the first case of an intrauterine treatment for cystic hygroma. Guided by ultrasonography, we first removed intracystic fluid from two cysts and then injected OK-432 into each fetal cyst at 21 and 28 weeks of gestation. No re-enlargement of the cysts was subsequently observed. At 38 weeks of gestation. a male infant was delivered transvaginally. Only a slight skin fold was observed in the nuchal area of the neonate, indicating the effectiveness of OK-432 for the intrauterine treatment of cystic hygroma.     

Successful treatment of severe fetal chylothorax resistant to repeated pleuroamniotic shunting by OK-432 pleurodesis

We report the first case of successful fetal pleurodesis with OK-432 for recurrent severe fetal primary chylothorax after failing repeated pleuroamniotic shunting. Shunting and pleurodesis could be complementary to each other in the treatment of fetal chylothorax.     

Treatment with biologic response modifiers in patients with ovarian cancer.

The therapeutic and immunomodulating potential of biological response modifiers (BRM) such as OK-432 (a streptococcal preparation) and recombinant interferon gamma (rIFN-gamma) has been evaluated in 15 patients with advanced chemotherapy resistant ovarian cancer, presenting malignant ascites and/or pleural effusions. OK-432 was injected intracavitary in 10 patients in increasing doses from 0.2 up to 7.5 mg weekly. Five women were treated intracavitary with rIFN-gamma twice a week. The initial dose was 0.1 mg/m2 which was raised up to 12 mg/m2 over 6 weeks. With OK-432 a complete response was achieved for 14.1 + 8.9 months in 4 patients, a partial response for 1.7 + 0.3 months in 3 patients. The survival time of the 4 responders was significantly longer (21.1 + 8.3 months) than the survival time of the patients with partial or no response (4.9 + 2.7,4.1 + 2.3 months, respectively). In the rIFN-gamma therapy group, we found a partial response in one and no response in 4 patients. Toxicity observed under OK-432 and rIFN-gamma was minimal in all patients, suggesting a lack of systemic effect of intracavitary-applied BRM. With both agents, augmentation of certain immune responses, especially in the peritoneal cavity and to a lesser extent in the peripheral blood, has been documented. In 5 patients treated with OK-432, we found an overall augmentation of the effusion macrophage killer activity. rIFN-gamma augmented natural killer activity in 2 of 3 patients.     

Prenatal DNA diagnosis of Noonan syndrome in a fetus with massive hygroma colli, pleural effusion and ascites

Prenatal molecular genetic diagnosis for Noonan syndrome I is reported. Noonan syndrome was suspected because of large cystic hygroma colli, massive pleural effusion and ascites at 23 weeks of gestation and normal karyotype (46,XX). DNA was prepared from amnion cells and screened for mutations in the PTPN11 gene. In exon 8, a missense mutation (S285F) was found. Delivery was induced at 33 weeks of gestation because of silent cardiotocography (CTG).Despite immediate drainage of the hydrothorax, mechanical ventilation was insufficient and the child died 9 h after birth due to severe pulmonary hypoplasia. Pleural punctate was enriched for small lymphocytes and thus was characterized as chylus.Prenatal ultrasound findings in Noonan syndrome usually are unspecific and rarely lead to a diagnosis. However, with the combination of cystic hygroma, pleural effusion, ascites and normal karyotype Noonan syndrome should be considered and DNA testing for PTPN11 mutations may be appropriate. Malformations of lymphatic vessels and/or chylothorax in Noonan syndrome seem to be more frequent than usually anticipated.     

Late-onset fetal bilateral pleural effusions associated with Down syndrome

Objective

We present two cases of late-onset bilateral fetal pleural effusions associated with fetal Down syndrome.

Pulmonary lymphangiomyomatosis complicating pregnancy. A case report

A 32-year-old primigravida presented with cough and dyspnea at 16 weeks' gestation. Chest roentgenogram revealed a large pleural effusion and diffuse interstitial infiltrates. Moderate arterial hypoxemia and a significant reduction in vital capacity were present. Thoracentesis revealed sterile chyle with no evidence of malignancy. Spontaneous delivery of a healthy infant occurred at 38 weeks, but no change was seen in either the pulmonary infiltrates or chylothorax. Open lung biopsy confirmed the clinical impression of pulmonary lymphangiomyomatosis, and a pleurodesis was performed. Progesterone and estrogen receptor assays on the lung biopsy material revealed only minimal binding. Following two years of therapy with tamoxifen citrate and megestrol acetate, the chylothorax has not recurred, and there has been no other appreciable change in pulmonary function.     

Langerhans cell histiocytosis: A rare aetiology for fetal pleural effusion

ObjectiveWe present fetal pleural effusions associated with Langerhans cell histiocytosis (LCH).Case reportWe report a case of fetal pleural effusion in late pregnancy. Due to developing rapidly over short period of time, the baby was delivered by caesarean section at 34 weeks gestation. Generalised oedema, sparse haemorrhagic papules, pulmonary involvement, mediastinal mass and liver dysfunction were identified postnatally. Structural malformations, maternal-fetal blood type incompatibility, chromosomal abnormalities and viral infection were excluded. Mediastinal mass biopsy and immunohistochemical examinations confirmed the diagnosis of Langerhans cell histiocytosis (LCH). The baby is currently in a stable condition and undergoing regular chemotherapy.ConclusionsCongenital LCH is a rare aetiology of fetal pleural effusions.     

Spontaneous regression and reaccumulation of pleural effusion in a fetus. A case report

Isolated pleural effusion is rare and occurs when varying degrees of fluid surround the fetal lung without concomitant hydrops. The effusion may regress spontaneously, remain stable in size, or progress to involve both sides of the chest causing fetal hydrops. This may result in pulmonary hypoplasia and fetal or neonatal demise. In this article, we report a case in which spontaneous resolution of an isolated right-sided fetal pleural effusion occurred at 23 weeks of gestation and reappeared bilaterally at 34 weeks. Serial ultrasonographic evaluation of the fetus should be continued even if a spontaneous resolution of a preexisting pleural effusion has occurred.     

Infected chylothorax caused by Streptococcus agalactiae: a case report.

Chylothorax is bacteriostatic in nature. Bacterial infection rarely develops in chylothorax and has never been reported in a non-immunocompromised host. A 33-year-old woman was admitted to National Taiwan University Hospital because of fever and right pleuritic pain. Chest roentgenography and computed tomography revealed right pleural effusion. Examination of the pleural effusion revealed a profile compatible with empyema and chylothorax. Culture of the pleural effusion yielded Streptococcus agalactiae. The woman was not immunocompromised. This is the first report of infected chylothorax caused by Streptococcus agalactiae in a non-immunocompromised host.     

Congenital chylothorax in neonatal thyrotoxicosis.

We report a patient with congenital chylothorax who also had neonatal thyrotoxicosis secondary to maternal Graves' disease. Fetal tachycardia with hydrops was detected at 28 weeks' gestational age. The fetus responded to antithyroid medication in utero but had persistent bilateral pleural effusion. At birth, he had respiratory distress due to massive pleural effusion. Cytologic studies of pleural fluid were consistent with chylothorax. To the best of our knowledge, the association of congenital chylothorax with fetal (neonatal) thyrotoxicosis, has not been reported previously.     

Successful early in utero management of fetal hydrothorax in a twin pregnancy

We present a case of dichorionic diamniotic twin pregnancy in which one of the fetuses was found to have a major pleural effusion at 15 weeks of gestation. A single-needle pleural fluid aspiration was performed at 15 and 16 weeks, but the fluid reaccumulated quickly after each procedure and at 16 weeks, the fetus was found to become progressively hydropic. A shunt was then successfully inserted at 17 weeks, which is the earliest gestation reported so far in the literature for such a procedure to treat isolated hydrothorax. Because we felt that the fetus would be too small for a classical double-pigtail pleuroamniotic shunt, we used a multilength double-pigtail bladder stent (Harrison drain; Cook; Spencer; Indiana; USA) via a 13-gauge echo tip trocar. This shunt could be used for both singleton and twin pregnancies presenting with fetal pleural effusion from as early as 16 to 17 weeks to prevent the development of fetal hydrops and polyhydramnios and subsequent premature delivery. Treatment at this stage of gestation would also minimize the risk of lung hypoplasia, which is the main clinical issue when shunts are inserted after 24 weeks.     

A case of large placental chorioangioma with non-immunological hydrops fetalis.

A 34-year-old Japanese woman (gravida 2, para 2) with polyhydramnios and non-immunological hydrops fetalis was referred to our department at 32 weeks of gestation. On admission, the blood pressure was 120/60 mmHg and there was no pitting edema of the lower extremities. An ultrasound examination disclosed a large placental tumor 5.8 cm x 4.4 cm x 4.8 cm. Fetal lung compression was suspected because the lung-thorax transverse area ratio was 0.13. The preload index of the inferior vena cava was 0.74, suggesting fetal cardiac failure. After fetal pleural effusion was aspirated, lung compression developed. Cordocentesis was performed at 33 weeks of gestation, and the fetal karyotype was confirmed to be 46, XY from an umbilical blood cultivation. The patient underwent a cesarean section at 33 weeks of gestation due to severe uterine contraction after preterm PROM. The baby was a 3,840 g male with a distended abdomen. Apgar score at 1 minute was 1. A chest X-ray demonstrated respiratory distress syndrome. The baby was discharged on the 69th day after birth and he is now 2 years and 9 months old and healthy.     

A rare case of posterior urethral valve and pleural effusion in Down syndrome with successful intrauterine shunt

Posterior urethral valve or pleural effusion accompanied with Down syndrome have been described previously; however, there is no reported case of posterior urethral valve and pleural effusion with Down syndrome. A 45-year-old multigravida woman was transferred due to bilateral fetal hydrothorax, polyhydramnios, and threatened preterm labor at 32 weeks' gestation. Transabdominal ultrasonography revealed additional abnormality, posterior urethral valve. Amniocentesis was repeated due to intense amniotic fluid and patient's dyspnea. Ultrasound-guided thoracoamniotic shunt and vesicoamniotic shunt were done successfully. At 33 weeks' gestation, intrauterine infection was suspected by the laboratory findings of amniotic fluid. A 2.25-kg male baby with characteristic phenotypic findings of Down syndrome was delivered by Cesarean section. Cytogenetic analysis after birth revealed a karyotype of 47,XY,+21. The present case reinforces the notions that fetuses with multiple anomalies, like congenital pleural effusion and posterior urethral valve, are at risk of chromosomal abnormalities, in spite of their low possibilities of association with chromosomal abnormalities.     

Proinflammatory macrophage migratory inhibition factor and interleukin-6 are concentrated in pleural effusion of human fetuses with prenatal chylothorax

OBJECTIVES: To study the role of selected cytokines and growth factors involved in the pathogenesis of fetal chylous pleural effusion. METHODS: Seventeen fetuses with prenatal chylothorax at gestational age (GA) 17-29 weeks were enrolled as the study group during the period 2003-2005. Their pleural effusion (n = 17) and amniotic fluid (n = 17) were drawn when disease set in. Eleven fetuses received cordocentesis because of suspected fetal anemia. Forty-one normal fetuses without adverse perinatal outcome at GA 17-29 weeks received amniocentesis and were enrolled in the reference group. Levels of hepatocyte growth factor (HGF), stromal-derived factor-1(SDF-1), vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), macrophage migratory inhibition factor (MIF), and interleukin-6 (IL-6) were determined in the samples from both groups (amniotic fluid, pleural fluid, and cord blood from the study group and amniotic fluid from the reference group) by enzyme-linked immunoassay (EIA). RESULTS: No significant differences were observed in the amniotic fluids between the study group and the reference group regarding levels of IL-6, IL-8, MIF, SDF-1, HGF and VEGF. In the study group, levels of IL-8, VEGF and SDF-1 (all pro-angiogenic) showed no significant differences between the amniotic fluid, cord blood and pleural effusion. The level of HGF (proangiogenic) was significantly higher in the amniotic fluid than in the cord blood or the pleural effusion, but there were no significant differences between the levels in the pleural fluid and in the cord blood. Interestingly, the levels of MIF and IL-6 (both are proinflammatory) in the amniotic fluid and in the pleural effusion were much higher than the levels in the cord blood. CONCLUSION: Our study demonstrated that the levels of pro-inflammatory proteins (MIF and IL-6) that we tested were higher in the fetal pleural effusion than in the fetal circulation, a phenomenon not observed in the levels of proangiogenic proteins (HGF, SDF-1, VEGF, IL-8). This result implies that inflammation-related proteins may be more relevant than the angiogenesis-related proteins in the local environment of accumulating pleural effusion, a prominent feature of prenatal chylothorax.     

Intrauterine therapy for the acutely enlarging fetal cystic hygroma

Enlarged fetal cystic hygroma is known to cause life-threatening complications such as fetal hydrops and neonatal respiratory difficulty. A 28-year-old Japanese woman, gravida 0, presented with fetal cystic hygroma at 23 weeks of gestation. There were no other structural malformations or hydrops detected by ultrasonographic examination. In addition, the karyotype was diagnosed as normal through amniotic fluid analysis. The cystic lesion showed acute enlargement and intrauterine sclerotherapy using OK-432 was performed at 26 weeks. The size of the cyst initially decreased, which was followed by a gradual increase. A viable 3,098 g male infant was delivered by cesarean section at 37 weeks without any other complications. The infant had no clinical difficulty during the neonatal period and later underwent a surgical removal of the remaining cystic lesion. Cases of fetal cystic hygroma showing acute enlargement without other complications are considered good candidates for intrauterine therapy to prevent subsequent complications.