Genome-wide gene expression analysis implicates the immune response and lymphangiogenesis in the pathogenesis of fetal chylothorax.

Fetal chylothorax (FC) is a rare condition characterized by lymphocyte-rich pleural effusion. Although its pathogenesis remains elusive, it may involve inflammation, since there are increased concentrations of proinflammatory mediators in pleural fluids. Only a few hereditary lymphedema-associated gene loci, e.g. VEGFR3, ITGA9 and PTPN11, were detected in human fetuses with this condition; these cases had a poorer prognosis, due to defective lymphangiogenesis. In the present study, genome-wide gene expression analysis was conducted, comparing pleural and ascitic fluids in three hydropic fetuses, one with and two without the ITGA9 mutation. One fetus (the index case), from a dizygotic pregnancy (the cotwin was unaffected), received antenatal OK-432 pleurodesis and survived beyond the neonatal stage, despite having the ITGA9 mutation. Genes and pathways involved in the immune response were universally up-regulated in fetal pleural fluids compared to those in ascitic fluids. Furthermore, genes involved in the lymphangiogenesis pathway were down-regulated in fetal pleural fluids (compared to ascitic fluid), but following OK-432 pleurodesis, they were up-regulated. Expression of ITGA9 was concordant with overall trends of lymphangiogenesis. In conclusion, we inferred that both the immune response and lymphangiogenesis were implicated in the pathogenesis of fetal chylothorax. Furthermore, genome-wide gene expression microarray analysis may facilitate personalized medicine by selecting the most appropriate treatment, according to the specific circumstances of the patient, for this rare, but heterogeneous disease.

2,4,6-trisubstituted triazines as protein a mimetics for the treatment of autoimmune diseases.

A first-in-class series of low molecular weight trisubstituted triazines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure-activity relationship (SAR) demonstrates that the 1,3-phenylenediamine component was essential for robust activity. Twenty-two compounds, represented by lead molecule 34, displayed significant activity compared to protein A. These compounds may prove useful for the treatment of autoimmune disease.

Spontaneous subcapsular hematoma of liver in pregnancy of unknown etiology--conservative management: a case report.

Mrs. AB, a 40-year-old woman, in her second pregnancy had a spontaneous hematoma of liver of unknown etiology that was managed successfully conservatively under the umbrella of the multidisciplinary care. The subcapsular hematoma was diagnosed at 31 weeks gestational age while she was being investigated because of sudden and gross drop of hemoglobin from 12.8 to 8 g/dl in 2 weeks duration. The dilemma remains as how to manage her future pregnancies and what are the risks of recurrence.

Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth.

OBJECTIVE: To estimate the relationship between maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in early pregnancy with the risk of subsequent adverse outcome. METHODS: A nested, case-control study was performed within a prospective cohort study of Down syndrome screening. Maternal serum levels of sFlt-1 and PlGF at 10-14 weeks of gestation were compared between 939 women with complicated pregnancies and 937 controls. Associations were quantified as the odds ratio for a one decile increase in the corrected level of the analyte. RESULTS: Higher levels of sFlt-1 were not associated with the risk of preeclampsia but were associated with a reduced risk of delivery of a small for gestational age infant (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.88-0.96), extreme (24-32 weeks) spontaneous preterm birth (OR 0.90, 95% CI 0.83-0.99), moderate (33-36 weeks) spontaneous preterm birth (OR 0.93, 95% CI 0.88-0.98), and stillbirth associated with abruption or growth restriction (OR 0.77, 95% CI 0.61-0.95). Higher levels of PlGF were associated with a reduced risk of preeclampsia (OR 0.95, 95% CI 0.90-0.99) and delivery of a small for gestational age infant (OR 0.95, 95% CI 0.91-0.99). Associations were minimally affected by adjustment for maternal characteristics. CONCLUSION: Higher early pregnancy levels of sFlt-1 and PlGF were associated with a decreased risk of adverse perinatal outcome.

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.

Management of cervical weakness based on the measurement of cervical resistance index.

OBJECTIVE: To assess the value of measuring cervical resistance index (CRI) as an aid to selecting patients with a history of spontaneous mid-trimester miscarriage for cervical cerclage in subsequent pregnancies. STUDY DESIGN: An observational study of 175 patients with a history of one or more spontaneous mid-trimester losses and 123 non-pregnant women who had CRI measurements performed while undergoing routine gynaecological surgery. Those women whose CRI indicated an incompetent cervix were recommended for cervical cerclage in future pregnancies while women with a normal CRI were recommended for conservative management without cerclage. RESULTS: The median CRI in the 123 control women was 38.26 N while the median CRI in the study group was 17.00 N. In 62 of the 175 study women (35%) the CRI findings were at variance with the history of previous mid-trimester loss; 30 (16.6%) were deemed competent on CRI whereas the history suggested incompetence and 32 (18.4%) were incompetent on CRI while the history suggested that the cervix should be competent. The 175 study women had had 486 previous pregnancies with a successful outcome in 27.4% of the pregnancies. Ninety-four patients have now had 148 pregnancies with a successful outcome in 75.8% of the pregnancies. CONCLUSIONS: Non-pregnant women with a history of spontaneous mid-trimester miscarriage have a significantly lower cervical resistance index than parous women who have not suffered mid-trimester loss. In 35% of patients the CRI was at variance with the history of the previous loss. CRI may be a useful technique to aid the diagnosis of cervical weakness allowing a rational selection for treatment with prophylactic cervical cerclage.

Severity of non-immune hydrops fetalis at birth continues to predict survival despite advances in perinatal care.

OBJECTIVES: To describe the aetiology and short-term outcome of live-born infants with non-immune hydrops fetalis (NIH), to identify predictors of mortality and to establish whether there has been any change in mortality over a 14-year period. METHODS: A retrospective case note review of all liveborn neonates with NIH. RESULTS: 30 infants were identified. Twenty (66%) had an identifiable aetiology. Ten (33%) survived to discharge. Survivors had significantly higher Apgar scores at 1 and 5 min (both p<0.001). Mortality did not differ between the time periods 1990-1999 and 2000-2004. CONCLUSIONS: NIH continues to be associated with a significant mortality despite advances in perinatal care. Poor condition at birth is a strong predictor of death.

Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome.

OBJECTIVE: To describe the association between pregnancy associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP) and adverse perinatal outcome. METHODS: We conducted a multicenter prospective cohort study of 8,483 women attending for prenatal care in southern Scotland between 1998 and 2000. The risk of delivering a small for gestational age infant, delivering preterm, and stillbirth were related to maternal serum levels of PAPP-A and AFP. RESULTS: Women with a low PAPP-A were not more likely to have elevated levels of AFP. Compared with women with a normal PAPP-A and a normal AFP, the odds ratio for delivering a small for gestational age infant for women with a high AFP was 0.9 (95% confidence interval [CI] 0.5-1.6), for women with a low PAPP-A was 2.8 (95% CI 2.0-4.0), and for women with both a high AFP and a low PAPP-A was 8.5 (95% CI 3.6-20.0). The odds ratio for delivering preterm for women with a high AFP was 1.8 (95% CI 1.3-2.7), for women with a low PAPP-A was 1.9 (95% CI 1.3-2.7), and for women with both a low PAPP-A and a high AFP was 9.9 (95% CI 4.4-22.0). These interactions were statistically significant for both outcomes (P = .03 and .04, respectively). There was a nonsignificant trend toward a similar interaction in relation to stillbirth risk. Of the women with the combination of a low PAPP-A and high AFP, 32.1% (95% CI 15.9-52.4) delivered a low birth weight infant. CONCLUSION: Low maternal serum levels of PAPP-A between 10 and 14 weeks and high levels of AFP between 15 and 21 weeks gestation are synergistically associated with adverse perinatal outcome. LEVEL OF EVIDENCE: II-2.

Rescue of the hypoplastic lung by prenatal cyclical strain.

We determined the effects of sustained and cyclical prenatal mechanical strain on the hypoplastic lung of the ovine model of congenital diaphragmatic hernia. Over a period of 4 weeks in late gestation, repeated cyclical tracheal occlusion for 23 hours with 1-hour release stimulated minimal growth, but promoted maturation with the development of a saccular lung. In contrast, a cycle consisting of 47 hours with 1-hour release induced optimal lung growth and morphologic maturation of the hypoplastic lung parenchyma. Sustained occlusion resulted in exaggerated lung growth, exceeding that of unaffected controls, and abnormal alveolar development. The extent of induction of lung growth by mechanical strain was inversely proportional to the number of alveolar type II cells remaining in the lung epithelium. These studies show that, although mechanical strain is capable of inducing lung growth and differentiation, cyclical strain is a prerequisite for normal development and that mechanically induced growth occurs at the expense of the alveolar type II cell. We conclude that cyclical strain may allow optimal alveolar development while maintaining a population of alveolar type II cells and may thus facilitate an improvement in postnatal lung function in infants with congenital diaphragmatic hernia.

First-trimester placentation and the risk of antepartum stillbirth.

CONTEXT: Preterm birth and low birth weight are determined, at least in part, during the first trimester of pregnancy. However, it is unknown whether the risk of stillbirth is also determined during the first trimester. OBJECTIVE: To determine whether the risk of antepartum stillbirth varies in relation to circulating markers of placental function measured during the first trimester of pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, prospective cohort study (conducted in Scotland from 1998 through 2000) of 7934 women who had singleton births at or after 24 weeks' gestation, who had blood taken during the first 10 weeks after conception, and who were entered into national registries of births and perinatal deaths. MAIN OUTCOME MEASURES: Antepartum stillbirths and stillbirths due to specific causes. RESULTS: There were 8 stillbirths among the 400 women with levels of pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile compared with 17 among the remaining 7534 women (incidence rate per 10,000 women per week of gestation: 13.4 vs 1.4, respectively; hazard ratio [HR], 9.2 [95% confidence interval [CI], 4.0-21.4]; P<.001). When analyzed by cause of stillbirth, low level of PAPP-A was strongly associated with stillbirth due to placental dysfunction, defined as abruption or unexplained stillbirth associated with growth restriction (incidence rate: 11.7 vs 0.3, respectively; HR, 46.0 [95% CI, 11.9-178.0]; P<.001), but was not associated with other causes of stillbirth (incidence rate: 1.7 vs 1.1, respectively; HR, 1.4 [95% CI, 0.2-10.6]; P = .75). There was no relationship between having a low level of PAPP-A and maternal age, ethnicity, parity, height, body mass index, race, or marital status. Adjustment for maternal factors did not attenuate the strength of associations observed. There was no association between maternal circulating levels of the free beta subunit of human chorionic gonadotropin and stillbirth risk. CONCLUSION: The risk of stillbirth in late pregnancy may be determined by placental function in the first 10 weeks after conception.

Evolution of a percutaneous fetoscopic access system for single-port tracheal occlusion.

BACKGROUND/PURPOSE: Prenatal tracheal occlusion currently is being assessed as a treatment modality for congenital diaphragmatic hernia (CDH). The development of a totally percutaneous fetoscopic access system would help avoid the need for maternal laparotomy and reduce the morbidity rate of fetal surgical procedures for the mother. Laparoscopic radial expansion sheaths and Seldinger technique-based vascular catheters both have been advocated as means of achieving amniotic cavity access. The authors have investigated these 2 systems in an attempt to develop a reliable method for achieving safe percutaneous fetoscopic access and present the first successful attempt to deploy an intratracheal balloon using an entirely percutaneous approach through a single port in an ovine model. METHODS: A number of prototype systems were evaluated sequentially over a 3-year period in an ovine model: (1) the radially expanding InnerDyne step port system, (2) a new rigid cannula with a bulbous/sharp end preloaded onto the radially expanding InnerDyne port, (3) a conical removable addition to the rigid cannula in 2, (4) a modified bulbous/sharp ended cannula incorporating a circumferential protective insert, (5) a rigid split sheath with the radially expanding port placed through the lumen of the split sheath, (6) a flexible introducer and dilator with the split sheath (used in the Seldinger placement of central lines), and (7) a 2-needle approach using a superelastic shape-memory alloy Nickel-Titanium wire with the flexible dilator and sheath, incorporating a side perfusion port. For balloon tracheal occlusion, live anaesthetized time-mated pregnant ewes were used at 110 days' gestation. Tracheobronchoscopy was achieved using a 3-mm 0 degrees telescope, and the cutaneotracheal tract was secured by a 3.3-mm sheath incorporating a side-perfusion port. The rigid telescope was replaced by a flexible choledochoscope preloaded with a silicone balloon. The balloon was deployed 2 cm above the carina proximal to the right upper lobe bronchus. RESULTS: The many problems encountered in the evolution of the preferred system related mainly to separation and tenting of the chorioamniotic membranes in the ovine uterus and inconsistent access to the fetal parts of interest. Each resulted in significant modifications to our approach. Furthermore, the use of rigid access devices commonly caused fetal injury. Successful access to the intrauterine cavity and cannulation of the trachea was achieved consistently with minimal trauma, irrespective of fetal position by method 7. Multiple port placement allowed visualization of the entry of all components of the system confirming minimal chorioamniotic membrane separation and tenting. Single port tracheal occlusion was undertaken first on 6 cadavers before being performed successfully on 3 live anaesthetized ewes. Fetoscopic access and cannulation of the trachea was achieved consistently in all live animals irrespective of fetal position. CONCLUSIONS: This modified Seldinger technique using the unique properties of the memory-shaped alloy wire for initial uterine access offers a safe method for the percutaneous placement of fetoscopic ports in the ovine model for prenatal intervention. Successful placement of a tracheal balloon entirely through a single percutaneously placed port represents a further advance in prenatal therapy for CDH.

Combined ultrasound and biochemical screening for Down's syndrome in the first trimester: a Scottish multicentre study.

OBJECTIVE: To evaluate the use of ultrasound measurements of fetal nuchal translucency (NT) obtained in a routine antenatal clinic setting in combination with appropriate biochemical markers as a first trimester screening test for Down's Syndrome. DESIGN: Multicentre observational study. SETTING: Fifteen Scottish maternity units. POPULATION: Pregnant women (n = 17,229) attending routine antenatal clinics at 10-14 weeks of gestation. METHODS: NT measurements were attempted in all women along with the measurement of maternal serum free beta human chorionic gonadotrophin (F beta hCG) and pregnancy-associated plasma protein-A (PAPP-A). All results were converted to multiples of the appropriate gestational median (MoM) and using a statistical model the risk of an affected pregnancy was derived. No results were given to participating women but all were offered routine second trimester biochemical screening. All cases of Down's Syndrome within the study group were ascertained and the detection rate for each marker was estimated. MAIN OUTCOME MEASURES: Success rate of obtaining NT measurements and overall effectiveness of ultrasound and biochemical markers individually and in combination for the detection of Down's Syndrome pregnancies. RESULTS: NT measurements were obtained in 72.9% of women and blood samples in 98.4%. Forty-five cases of Down's Syndrome were ascertained (2.6/1,000). NT measurements were obtained in 37 cases (median NT 1.65 MoM), blood samples in 42 cases and both NT and blood in 34 cases. In combination with the a priori maternal age risk, observed detection rates at a 5% false positive rate were 20/37 (54%) for NT, 23/42 (55%) for F beta hCG and PAPP-A and 28/34 (82%) for a combination of NT, F beta hCG and PAPP-A using a cutoff risk of 1:250. The effect of failing to obtain NT measurements in all cases reduces the overall detection rate to 62% (i.e. 28/45) if the entire series of affected pregnancies within the study group is considered. CONCLUSIONS: NT in combination with appropriate serum markers has the potential to detect over 80% of Down's Syndrome fetuses in early pregnancy. However, NT measurement is highly operator-dependent. It requires training, external quality control and adequate time to allow accurate measurement, otherwise suboptimal performance will result.

Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies.

CONTEXT: Trial of labor after previous cesarean delivery is associated with increased risk of uterine rupture. However, no reliable data exist on the effect of a trial of labor on the risk of perinatal death in otherwise uncomplicated term pregnancies. OBJECTIVE: To determine the risk of intrapartum stillbirth or neonatal death not related to congenital abnormality among women with uncomplicated term pregnancies who had a trial of labor after previous cesarean delivery, compared with women having a planned repeat cesarean delivery, and multiparous and nulliparous women at term not delivered by planned cesarean method. DESIGN AND SETTING: Population-based, retrospective cohort study of data from the linked Scottish Morbidity Record and Stillbirth and Neonatal Death Enquiry encompassing births in Scotland between January 1, 1992, and December 31, 1997. POPULATION: A total of 313 238 singleton births between 37 and 43 weeks' gestational age in which the fetus was in a cephalic presentation. MAIN OUTCOME MEASURE: Delivery-related perinatal death, defined as intrapartum stillbirth or neonatal death unrelated to congenital anomaly, compared among the 4 groups. RESULTS: Among women who had a trial of labor following previous cesarean delivery (n = 15 515), the overall rate of delivery-related perinatal death was 12.9 (95% confidence interval [CI], 7.9-19.9) per 10 000 women. This was approximately 11 times greater (odds ratio [OR], 11.6; 95% CI, 1.6-86.7) than the risk associated with planned repeat cesarean delivery (n = 9014), more than twice (OR, 2.2; 95% CI, 1.3-3.5) the risk associated with other multiparous women in labor (n = 151 549), and similar to the risk among nulliparous women in labor (n = 137 160; OR, 1.3; 95% CI, 0.8-2.1). The associations were not explained by differences in maternal height, smoking status, socioeconomic status, age, fetal growth, or week of gestation at delivery. Among women having a trial of labor, the rate of death due to mechanical causes, including uterine rupture, was 4.5 (95% CI, 1.8-9.3) per 10 000 women. This was more than 8 times greater than other multiparous women (OR, 8.5; 95% CI, 3.2-22.3) and nulliparous women (OR, 8.8; 95% CI, 3.2-24.2). CONCLUSIONS: The absolute risk of perinatal death associated with trial of labor following previous cesarean delivery is low. However, in our study, the risk was significantly higher than that associated with planned repeat cesarean delivery, and there was a marked excess of deaths due to uterine rupture compared with other women in labor.

Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth.

The risk of adverse perinatal outcome among 8839 women recruited to a multicenter, prospective cohort study was related to maternal circulating concentrations of trophoblast-derived proteins at 8-14 wk gestation. Women with a pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile at 8-14 wk gestation had an increased risk of intrauterine growth restriction [adjusted odds ratio, 2.9; 95% confidence interval (CI), 2.0-4.1], extremely premature delivery (adjusted odds ratio, 2.9; 95% CI, 1.6-5.5), moderately premature delivery (adjusted odds ratio, 2.4; 95% CI, 1.7-3.5), preeclampsia (adjusted odds ratio, 2.3; 95% CI, 1.6-3.3), and stillbirth (adjusted odds ratio, 3.6; 95% CI, 1.2-11.0). The strengths of the associations were similar when the test was performed before 13 wk gestation or between 13 and 14 wk gestation. In contrast, levels of free beta-human CG, another circulating protein synthesized by the syncytiotrophoblast, were not predictive of later outcome in multivariate analysis. PAPP-A has been identified as a protease specific for IGF binding proteins. We conclude that control of the IGF system in the first and early second trimester trophoblast may have a key role in determining subsequent pregnancy outcome.