Guoyang Luo

Progesterone Inhibits Basal and TNF-α-Induced Apoptosis in Fetal Membranes: A Novel Mechanism to Explain Progesterone-Mediated Prevention of Preterm Birth

Objective: Progesterone supplementation prevents preterm birth (PTB) in some high-risk women, but its mechanism of action is not known. One third of PTB is associated with preterm premature rupture of membranes (PPROM). We hypothesize that progesterone may block proinflammatory cytokine-induced apoptosis of fetal membrane, thereby preventing PPROM and PTB. Methods: Fetal membranes were collected at elective repeat cesarean at term (no labor, no infection [n = 12]), washed, and cultured with/ without progesterone (125-500 ng/mL), 17α-hydroxyprogesterone caproate (125-500 ng/mL [17P]), or medroxyprogesterone acetate (10-7-10 -6 mol/L [MPA]) for 24 hours. Membranes were then treated with/without lipopolysaccharide ([LPS] 100 ng/mL) or tumor necrosis factor alpha ([TNF-α] 50 ng/ mL) for 24 to 72 hours, harvested, and homogenized. Apoptosis was determined by evaluating caspase-3, -8, and -9 activities. Caspase activity in relative light units was measured on a luminometer and corrected for total protein. Results: Both TNF-α and LPS significantly increased caspase-3, -8, and -9 activity in term fetal membranes in a time-dependent fashion. Progesterone, 17P, and MPA significantly reduced TNF-α, but not LPS, induced caspase-3 activity. Interestingly, progesterone and MPA, but not 17P, also inhibited basal caspase-3 activity. Conclusion: Progesterone inhibits basal and TNF-α-induced apoptosis in term fetal membranes. This novel observation may explain in part the mechanism by which progesterone supplementation prevents PPROM and PTB in some high-risk women. The effect of progesterone on the basal levels of apoptosis suggests that this mechanism may also be important for normal labor at term.

Prenatal diagnosis of congenital vascular rings and slings: sonographic features and perinatal outcome in 81 consecutive cases.

To describe the sonographic features and perinatal outcome of congenital vascular rings diagnosed prenatally at a single tertiary care institution.

Intra-amniotic Infection Upregulates Neutrophil Gelatinase-Associated Lipocalin (NGAL) Expression at the Maternal-Fetal Interface at Term: Implications for Infection-Related Preterm Birth

Objective: Neutrophil gelatinase-associated lipocalin (NGAL) is a ubiquitous lipocalin that serves as a critical component of innate immunity and a transport shuttle for numerous substances (retinoids, arachidonic acid, prostaglandins, fatty acids, steroids, iron, and MMPs). Despite the well-documented association between intra-amniotic infection/inflammation (IAI) and preterm birth, NGAL expression in the uterus has not previously been examined. This study investigates NGAL expression at the maternal-fetal interface in vivo and in vitro. Methods: Neutrophil gelatinase-associated lipocalin expression in term placenta with/without IAI was examined by immunohistochemistry. Trophoblast and decidual stromal cells were retrieved from elective cesarean, purified, and depleted of leukocytes. On days 1 (cytotrophoblast cells) and 4 (syncytiotrophoblast), cells were stimulated with/without interleukin 1β (IL-1β; 1 ng/mL), tumor necrosis factor α (TNF-α; 1 ng/mL), or lipopolysaccharide (LPS; 1 μg/mL). Neutrophil gelatinase-associated lipocalin messenger RNA (mRNA) and protein expression were measured by immunocytochemistry/Western blot and RT-qPCR, respectively. Results: Under basal conditions, NGAL is expressed in trophoblast, but not decidua. Trophoblast NGAL is significantly upregulated in tissues with evidence of IAI vs controls. NGAL expression was increased after stimulation with all 3 pro-inflammatory mediators in day 1 (cytotrophoblast) but not day 4 cells (syncytiotrophoblast). IL-1β and TNF-α (not LPS) upregulated NGAL gene expression in cytotrophoblast (not syncytiotrophoblast) cells. Conclusions: Intra-amniotic infection/inflammation is associated with increased expression of NGAL in trophoblast tissues in vivo. IL-1β, TNF-α, and LPS stimulated NGAL in cytotrophoblast cells (not syncytiotrophoblast and decidua) in vitro. These data suggest that, in keeping with its role as a mediator of innate immunity, NGAL may have a central role to play in IAI-induced preterm birth.

Intra-amniotic infection upregulates decidual cell vascular endothelial growth factor (VEGF) and neuropilin-1 and -2 expression: implications for infection-related preterm birth.

Intra-amniotic infection/inflammation (IAI) is a major cause of preterm birth, but the mechanisms responsible are not well understood. This study investigates the effects of IAI on vascular endothelial growth factor (VEGF) as well as VEGF receptor (Flt1, KDR2) and coreceptor (neuropilin-1 and -2) messenger RNA (mRNA) and protein expression at the maternal-fetal interface, both in vitro and in vivo. Decidual stromal cells (DSCs) were isolated from term placentae, purified, and treated with 10—8 mol/L estradiol (E2), 10 —7 mol/L medroxyprogesterone acetate (MPA), both, or vehicle for 7 days. Vascular endothelial growth factor expression in cultured DSCs increased in response to stimulation with interleukin 1β (IL-1β; 0.01-10 ng/mL)—but not tumor necrosis factor α (TNF-α; 1 ng/mL)—in a concentration-dependent fashion irrespective of the hormonal milieu. This effect appears to be mediated at the level of gene transcription because stimulation with IL-1β (but not TNF-α) increased expression of VEGF mRNA as measured by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR); a similar increase was seen in neuropilin-1/-2 (but not Flt1 and KDR2) mRNA. Immunohistochemical studies confirmed these observations in vivo. Immunostaining for VEGF and neuropilin-1/-2 (but not Flt1 or KDR2) was increased in serial tissue sections of decidua from women with clinical and histological evidence of IAI versus noninfected controls, and in cultured term DSCs exposed to IL-1β. The novel observations that IL-1β stimulates VEGF and neuropilin-1/-2 mRNA and protein expression in term DSCs in vitro along with confirmatory in vivo data using immunohistochemistry provide a mechanism by which IAI can alter vascular permeability, thereby facilitating leukocyte trafficking and increasing the risk of abruption, both of which are associated with preterm birth.

Single nucleotide polymorphisms in the human progesterone receptor gene and spontaneous preterm birth.

Progesterone supplementation can prevent preterm birth in some high-risk women. Progesterone binds to progesterone receptor (PR) and modulates the expression of target genes. This study investigates the association between single nucleotide polymorphisms (SNPs) in the PR gene and spontaneous preterm birth. DNA was extracted from consecutive patients with preterm birth (n = 78) and term controls (n = 415), and genotyping was performed for 3 PR SNPs (+331[G>A], + 770[C>T], +660[G>T]) using Sequenom matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed by χ 2 test and logistic regression analysis. Multivariate analysis showed no association between maternal carriage of minor + 331T, +770T, and/or +660T alleles and preterm birth when controlled for maternal age, ethnicity, gravidity, parity, prior preterm birth, route of delivery, or neonatal outcome. Carriage of +770T and +660T (but not +331T) was associated with preterm birth in women with a body mass index <18.5 kg/m2 (relative risk, 10.8; 95% confidence interval, 1.4-82.6; P = .02). Maternal carriage of minor alleles of +331(G>A), +770(C>T), and +660(G> T) SNPs in the PR gene is not associated with spontaneous preterm birth.

Spontaneous Rupture of the Spleen: A Rare but Serious Case of Acute Abdominal Pain in Pregnancy

BACKGROUND Spontaneous (non-traumatic) rupture of the spleen rarely occurs in the setting of a normal spleen, especially during pregnancy. OBJECTIVES We report a case of spontaneous rupture of a normal spleen at 33.7 weeks gestation and review the literature with the aim of exploring the etiology, diagnosis, and management of this condition during pregnancy. CASE REPORT A 30-year-old Chinese primigravida presented at 33.7 weeks gestation with acute onset of severe, constant left upper abdominal pain. She developed acute hypotension. Physical examination revealed diffuse abdominal tenderness with rebounding and guarding. An emergent cesarean delivery and abdominal exploration was performed. A non-viable male infant was delivered, and active bleeding was identified at the splenic hilum consistent with splenic rupture. A splenectomy was performed, and a consumptive coagulopathy was identified and treated. The patient had an uncomplicated postoperative course and was discharged home on postoperative day 15. CONCLUSION Splenic rupture in pregnancy is a life-threatening complication. Early diagnosis and aggressive surgical intervention will allow for optimal maternal and perinatal outcome.

Fetal renal artery impedance as assessed by Doppler ultrasound in pregnancies complicated by intraamniotic inflammation and preterm birth

OBJECTIVE The objective of the study was to evaluate the fetal renal artery impedance in the context of inflammation-associated preterm birth. STUDY DESIGN We conducted a prospective Doppler assessment of the fetal renal artery impedance in 70 singleton fetuses. The study group consisted of 56 premature fetuses (median, 28.1 [interquartile range, 25.3-30.6] weeks at enrollment). Gestational age (GA) reference ranges were generated based on fetuses with uncomplicated pregnancies (n = 14). Doppler studies included renal artery pulsatility index (PI), resistance index (RI), systolic/diastolic (S/D) ratio, and presence or absence of end-diastolic blood flow. Proteomic profiling (surface-enhanced laser desorption ionization time-of-flight) was used for assessment of intraamniotic inflammation and biomarker peak corresponding to beta2-microglubin. Data were interpreted in relationship to amniotic fluid index (AFI), cord blood interleukin (IL)-6 and erythropoietin (EPO) levels. The cardiovascular and metabolic profiles of the neonates were investigated in the first 24 hours of life. RESULTS Fetuses delivered by mothers with intraamniotic inflammation had higher cord blood IL-6 but not EPO levels. Fetal inflammation did not affect either renal artery PI, RI, S/D ratio, or end-diastolic blood flow. Neonates delivered in the context of intraamniotic inflammation had higher serum blood urea nitrogen levels, which correlated significantly with AF IL-6 levels. The renal artery RI and SD ratio were inversely correlated with the AFI independent of GA, cord blood IL-6, and status of the membranes. CONCLUSION The fetus is capable of sustaining normal renal artery impedance despite inflammation. Resistance in the renal vascular bed affects urine output independent of inflammation.

The role of doppler waveforms in the fetal main pulmonary artery in the prediction of neonatal respiratory distress syndrome.

To describe changes in the Doppler waveforms of the fetal main pulmonary artery (MPA) throughout gestation and to assess their predictive value of neonatal respiratory distress syndrome (RDS).

Prenatal diagnosis and perinatal outcome of congenital dacryocystocele: a large case series.

To describe the incidence, prenatal diagnosis, and perinatal outcome in fetuses with congenital dacryocystocele.

Prenatal diagnosis of criss-cross heart: sonographical and pathological features of five cases

Objective:To describe the sonographical and pathological features of fetal criss-cross heart (CCH).Study Design:All cases of fetal CCH diagnosed by fetal echocardiogram from May 2003–May 2011 were identified at a single referral center using an established perinatal database. Demographic and genetic information, sonographical images and autopsy reports were reviewed. Sonographical and pathological features are described.Result:Five cases of fetal CCH were identified, all of which were confirmed by autopsy. Characteristic sonographical findings include: (1) the inability to obtain four-chamber view at standard transverse plane through the fetal chest; (2) appreciation of the misaligned spatial atrial–ventricle connection with the interventricular septum in a ‘spiraling’ orientation; (3) orientation of the two ventricular inlets in a superior–inferior and crossing position; and (4) a four-chamber-like view seen in the sagittal plane of the fetal chest. Doppler ultrasound demonstrates the ‘criss-cross’ arrangement of the inflow tracts into the two ventricles simultaneously in the transverse plane of the fetal chest.Conclusion:CCH is a rare developmental disorder that can be accurately diagnosed prenatally. Early diagnosis will allow for more targeted counseling and early intervention.