Fibroblast growth factor receptor 2 (FGFR2) is a crucial regulator of bone formation during embryonic development. Both gain and loss-of-function studies in mice have shown that FGFR2 maintains a critical balance between the proliferation and differentiation of osteoprogenitor cells. We have identified de novo FGFR2 mutations in a sporadically occurring perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Histological analysis of the long bones revealed that the growth plate contained smaller hypertrophic chondrocytes and a thickened hypercellular periosteum. Four unrelated affected individuals were found to be heterozygous for missense mutations that introduce a polar amino acid into the hydrophobic transmembrane domain of FGFR2. Using diseased chondrocytes and a cell-based assay, we determined that these mutations selectively reduced plasma-membrane levels of FGFR2 and markedly diminished the receptor's responsiveness to extracellular FGF. All together, these clinical and molecular findings are separate from previously characterized FGFR2 disorders and represent a distinct skeletal dysplasia.

Metatropic dysplasia is a clinical heterogeneous skeletal dysplasia characterized by short extremities, a short trunk with progressive kyphoscoliosis, and craniofacial abnormalities that include a prominent forehead, midface hypoplasia, and a squared‐off jaw. Dominant mutations in the gene encoding TRPV4, a calcium permeable ion channel, were identified all 10 of a series of metatropic dysplasia cases, ranging in severity from mild to perinatal lethal. These data demonstrate that the lethal form of the disorder is dominantly inherited and suggest locus homogeneity in the disease. Electrophysiological studies demonstrated that the mutations activate the channel, indicating that the mechanism of disease may result from increased calcium in chondrocytes. Histological studies in two cases of lethal metatropic dysplasia revealed markedly disrupted endochondral ossification, with reduced numbers of hypertrophic chondrocytes and presence of islands of cartilage within the zone of primary mineralization. These data suggest that altered chondrocyte differentiation in the growth plate leads to the clinical findings in metatropic dysplasia. © 2010 Wiley‐Liss, Inc.

Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type 1 procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type 1 procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the alpha 1 (I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type 1 procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI.

The spondylometaphyseal dysplasias (SMDs) are a group of short-stature disorders distinguished by abnormalities in the ver-tebrae and the metaphyses of the tubular bones. SMD Kozlowski type (SMDK) is a well-defined autosomal-dominant SMD characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles similar to autosomal-dominant brachyolmia, which can result from heterozygosity for activating mutations in the gene encoding TRPV4, a calcium-permeable Ion channel. Mutation analysis in six out of six patients with SMDK demonstrated heterozygosity for missense mutations in TRPV4, and one mutation, predicting a R594H substitution, was recurrent in four patients. Similar to autosomal-dominant brachyolmia, the mutations altered basal calcium channel activity in vitro. Metatropic dysplasia is another SMD that has been proposed to have both clinical and genetic heterogeneity. Patients with the nonlethal form of metatropic dysplasia present with a progressive scoliosis, widespread metaphyseal involvement of the appendicular skeleton, and carpal ossification delay. Because of some similar radiographic features between SMDK and metatropic dysplasia, 'FRPV4 was tested as a disease gene for nonlethal metatropic dysplasia. In two sporadic cases, heterozygosity for de novo missense mutations in TRPV4 was found. The findings demonstrate that mutations in TRPV4 produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal-dominant brachyolmia to SMDK to autosomal-dominant metatropic dysplasia, suggesting that these disorders should be grouped into a new bone dysplasia family.

The short-rib polydactyly (SRP) syndromes are a heterogenous group of perinatal lethal skeletal disorders with polydactyly and multisystem organ abnormalities. Homozygosity by descent mapping in a consanguineous SRP family identified a genomic region that contained DYNC2H1, a cytoplasmic dynein involved in retrograde transport in the cilium. Affected individuals in the family were homozygous for an exon 12 missense mutation that predicted the amino acid substitution R587C. Compound heterozygosity for one missense and one null mutation was identified in two additional nonconsanguineous SRP families. Cultured chondrocytes from affected individuals showed morphologically abnormal, shortened cilia. In addition, the chondrocytes showed abnormal cytoskeletal microtubule architecture, implicating an altered microtubule network as part of the disease process. These findings establish SRP as a cilia disorder and demonstrate that DYNC2H1 is essential for skeletogenesis and growth.

OBJECTIVE:To investigate the prevalence of obesity and associated cardiovascular risk factors in schoolchildren in our city, given the influence of these factors on the development of atherosclerosis.METHODS:We studied a representative sample of second grade students composed of 370 children aged 7.82+/-0.62 years (47.8% girls and 52.2% boys); 52.4% were from public schools and 47.6% were from private schools. Surveys were performed and anthropometric measurements, blood pressure (BP) values and glucose and lipid profiles in capillary blood were determined.RESULTS:A total of 9.7% (36 schoolchildren) were obese and 13.8% were overweight. There were no differences according to sex or school system. Abdominal obesity was observed in 69.4% (p<0.0001), normal-high BP (90-97th percentile) in 27.8% (p<0.0001), dyslipidemia in 66.7% (p<0.05) and metabolic syndrome in 38.9% (p<0.0001) of the obese children compared with 1.3%, 5.1%, 48.9% and 0.4% of the children with normal weight, respectively. No association was found between fasting hyperglycemia and obesity. There were no cases of hypertension or diabetes mellitus. The risk (odds ratio) for normal-high BP, dyslipidemia, abdominal obesity and metabolic syndrome was 6.3, 2.2, 60.9, and 70.2 times higher in obese children than in non-obese children, respectively. A positive and significant correlation was found between waist circumference and body mass index with BP and the atherogenic indexes triglycerides/high-density lipoprotein cholesterol (HDL-C), total cholesterol/HDL-C and low-density lipoprotein cholesterol/HDL-C (p=0.0001).CONCLUSIONS:Compared with cities in other countries, the city of Mérida, Venezuela, has an intermediate prevalence of overweight and obesity in schoolchildren. The high frequency of cardiovascular risk factors in the obese and its positive correlation with adiposity highlights the need to implement population-based strategies for its prevention in childhood.

Objective. Heat shock protein (HSP) 70, a conserved member of the stress protein family, is produced in almost all cell types in response to a wide range of stressful stimuli, and its production has a survival value. Evidence suggests that extracellular HSP70 is involved in the activation of the innate and adaptive immune response. Furthermore, increased mRNA expression of HSP70 has been observed in human fetal membranes following endotoxin stimulation. This study was conducted to determine the changes in amniotic fluid HSP70 concentrations during pregnancy, term and preterm parturition, intra-amniotic infection (IAI), and histologic chorioamnionitis.Study design. A cross-sectional study was conducted in 376 pregnant women in the following groups: (1) women with a normal pregnancy who were classified into the following categories: (a) women in the mid-trimester (14–18 weeks) who underwent amniocentesis for genetic indications and delivered normal infants at term (n=72); (b) women at term not in labor (n = 23); and (c) those at term in labor (n = 48). (2) Women with spontaneous preterm labor and intact membranes who were subdivided into the following categories: (a) preterm labor who delivered at term without IAI (n = 42); (b) preterm labor who delivered preterm without IAI (n = 57); and (c) preterm labor and delivery with IAI (n = 30). (3) Women with preterm prelabor rupture of membranes (PROM) with (n = 50) and without (n = 54) IAI. Among patients with preterm labor with intact membranes and preterm PROM who delivered within 72 hours of amniocentesis, placenta, umbilical cord, and chorioamniotic membranes were collected and assessed for the presence or absence of acute inflammatory lesions in the extraplacental membranes (histologic chorioamnionitis) and/or umbilical cords (funisitis). HSP70 concentrations in amniotic fluid were determined using a sensitive and specific immunoassay. Non-parametric statistics were used for analysis. A p value of <0.05 was considered statistically significant.Results. Immunoreactive HSP70 was detected in 88% (332/376) of amniotic fluid samples. The median amniotic fluid HSP70 concentration was significantly higher in women at term without labor than in those in the mid-trimester (term no labor: median 34.9 ng/mL, range 0–78.1 ng/mL vs. mid-trimester; median 6.6 ng/mL, range 0–20.8 ng/mL; p<0.001). Among patients with spontaneous preterm labor and preterm PROM, those with IAI had a significantly higher median amniotic fluid HSP70 concentration than those without IAI (preterm labor with IAI: median 82.9 ng/mL, range 0–500 ng/mL vs. preterm labor without IAI: median 41.7 ng/mL, range 0–244 ng/mL; p = 0.001; preterm PROM with IAI: median 86.5 ng/mL, range 0–428 ng/mL vs. preterm PROM without IAI: median 55.9 ng/mL, range 14.9–299.9 ng/mL; p = 0.007). There was no significant difference in the median amniotic fluid HSP70 concentration between patients with preterm labor who delivered preterm without IAI and those who delivered at term (p = 0.6). However, among patients with preterm labor without IAI, there was an inverse relationship between amniotic fluid concentration of HSP70 and the amniocentesis-to-spontaneous delivery interval (Spearman's Rho = −0.26; p = 0.02). Patients with histologic chorioamnionitis/funisitis had a significantly higher median amniotic fluid HSP70 concentration than those without inflammation (inflammation: median 108.7 ng/mL, range 0–500 ng/mL vs. without inflammation: median 67.9 ng/mL, range 7.1–299.9 ng/mL; p = 0.02). Women at term in labor had a median amniotic fluid concentration of HSP70 significantly higher than those not in labor (term in labor: median 60.7 ng/mL, range 0–359.9 ng/mL vs. term not in labor: median 34.9 ng/mL, range 0–78.1 ng/mL; p = 0.02).Conclusions. Intra-amniotic infection, histologic chorioamnionitis, and term parturition are associated with elevated amniotic fluid HSP70 concentrations. HSP70 plays a role in the host defense mechanism by activating the innate arm of the immune response in women with intrauterine infection. The mechanisms of preterm and term parturition in humans may involve extracellular HSP70.

Objective. Intra-amniotic infection/inflammation (IAI) is one of the most important mechanisms of disease in preterm birth. Resistin is an adipocytokine that has been linked to insulin resistance, diabetes, obesity and inflammation. The objective of this study was to determine if resistin is present in amniotic fluid (AF) and if its concentration changes with gestational age, in the presence of labour, and in IAI in patients with spontaneous preterm labour (PTL) and intact membranes, preterm prelabour rupture of membranes (PPROM) and clinical chorioamnionitis.Study design. This cross-sectional study included 648 patients in the following groups: (1) women in the mid-trimester of pregnancy (14–18 weeks) who underwent amniocentesis for genetic indications and delivered a normal neonate at term (n = 61); (2) normal pregnant women at term with (n = 49) and without (n = 50) spontaneous labour; (3) patients with an episode of PTL and intact membranes who were classified into: (a) PTL who delivered at term (n = 153); (b) PTL who delivered preterm (<37 weeks gestation) without IAI (n = 108); and (c) PTL with IAI (n = 84); (4) women with PPROM with (n = 47) and without (n = 44) IAI; and (5) patients with clinical chorioamnionitis at term with (n = 22) and without (n = 30) microbial invasion of the amniotic cavity. Resistin concentration in AF was determined by enzyme-linked immunoassay. Non-parametric statistics were used for analyses.Results. (1) Resistin was detected in all AF samples; (2) the median AF resistin concentration at term was significantly higher than in the mid-trimester (23.6 ng/mL vs. 10 ng/mL; p < 0.001); (3) among patients with PTL, the median AF resistin concentration was significantly higher in patients with IAI than in those without IAI (144.9 ng/mL vs. 18.7 ng/mL; p < 0.001) and those with PTL and intact membranes who delivered at term (144.9 ng/mL vs. 16.3 ng/mL; p < 0.001); (4) patients with PPROM with IAI had a significantly higher median AF resistin concentration than those without IAI (132.6 ng/mL vs. 13 ng/mL; p < 0.001); (5) no significant differences were observed in the median AF resistin concentration between patients with spontaneous labour at term and those at term not in labour (28.7 ng/mL vs. 23.6 ng/mL; p = 0.07); and (6) AF resistin concentration ≥37 ng/mL (derived from a receiver-operating characteristic curve) had a sensitivity of 85.4% and a specificity of 94.3% for the diagnosis of intra-amniotic inflammation.Conclusions. Resistin is a physiologic constituent of the AF, and its concentrations in AF: (1) are significantly elevated in the presence of IAI; (2) increase with advancing gestation; and (3) do not change in the presence of spontaneous labour at term. We propose that resistin may play a role in the innate immune response against intra-amniotic infection.

Pre-eclampsia (PE) is thought to be causally related to an “anti-angiogenic state” characterized by increased concentrations of soluble endoglin (Nature Medicine 2006; 12: 642–9) and soluble VEGFR-1 (NEJM 2004; 350 : 672–83). This “anti-angiogenic state” may be reflected by changes in the impendence to flow in the maternal and fetal circulations. The objective of this study was to examine the relationship between abnormalities in uterine (UT) and/or umbilical artery (UA) Doppler velocimetry and maternal plasma concentration of the powerful anti-angiogenic factor, endoglin, in patients with PE. A cross-sectional study was conducted in normal pregnant women (n = 135) and patients with PE (n = 69). Patients with PE were sub-classified into four groups according to the results of UT and UA artery Doppler velocimetry. Plasma concentrations of soluble endoglin (sEng) were determined by ELISA. 1) Patients with an abnormal UT and UA Doppler velocimetry had the highest median plasma concentration of sEng than any other diagnostic group (Kruskal Wallis P < 0.05, see table); 2) Women with PE and normal Doppler velocimetry in both vessels had the lowest median plasma concentration of sEng; 3) Plasma sEng concentrations increased as a function of gestational age (GA) (Spearman's rho = 0.4; P < 0.001). Yet, the patients with the highest median sEng concentration were those with abnormal maternal and fetal Doppler velocimetry and the lowest GA (P < 0.05). Abnormalities of impedance to blood flow in the uterine and umbilical circulation are associated with an excess of sEng in the circulation of mothers with PE. These findings suggest that the severity of the anti-angiogenic state in PE is expressed by abnormalities of Doppler velocimetry.

ProblemMannose-binding lectin (MBL) is a pattern-recognition receptor that activates complement and modulates inflammation. Homozygosity for the most common allele of the MBL2 gene that is associated with high MBL serum concentrations is more prevalent among patients with pre-eclampsia. The objective of this study was to determine maternal plasma MBL concentrations in normal pregnant women and patients with pre-eclampsia.Method of studyThis cross-sectional study included normal pregnant women (n = 187) and patients with pre-eclampsia (n = 99). Maternal plasma MBL concentrations were determined by ELISA.ResultsWomen with pre-eclampsia had a higher median maternal plasma MBL concentration than normal pregnant women. MBL concentration distribution curves were three-modal, the subintervals in normal pregnancy were low (< 143.7), intermediate (143.7-1898.9) and high (> 1898.9 ng/mL). The proportion of normal pregnant women was larger in the low subinterval, while the proportion of patients with pre-eclampsia was larger in the high subinterval (P = 0.02). Normal pregnant women in the high subinterval had a larger rate of placental underperfusion than those in the low and intermediate subintervals (P = 0.02).ConclusionsThe median maternal plasma MBL concentration is elevated in patients with pre-eclampsia and a larger proportion of these patients are in the high subinterval than normal pregnant women, suggesting that this component of the innate immune system is involved in the mechanisms of disease in pre-eclampsia.

Utero-placental ischemia has been implicated as one of the mechanisms of disease in SGA. Recently, an anti-angiogenic state (reflected by elevation of soluble endoglin concentrations in maternal blood) has been described in mothers with SGA fetuses without preeclampsia and detected as early as the first trimester of pregnancy. The objective of this study was to determine if mothers of SGA fetuses with and without Doppler abnormalities have different profiles of the anti-angiogenic factor, soluble endoglin (sEng). A cross-sectional study was conducted in 46 pregnancies which led to the birth of SGA neonates. SGA were sub-classified according to the results of uterine (UT) and umbilical (UA) artery Doppler velocimetry. The control group consisted of normal pregnant women who delivered appropriate for gestational age neonates (n = 135). Plasma concentrations of sEng were determined by a sensitive and specific immunoassay. 1) Mothers with SGA fetuses with an abnormal Doppler velocimetry (in the UT or the UA) had a higher median plasma concentration of sEng than those without these abnormalities (both P < 0.05; see Table); 2) Mothers with SGA fetuses and abnormal UA Doppler velocimetry (utero-placental insufficiency) had higher sEng concentrations than both mothers with SGA fetuses with normal Doppler velocimetry and the control group (P < 0.05 for both). An increased impedance to blood flow in the umbilical circulation and in the uterine circulation is strongly associated with an excess availability of the anti-angiogenic factor in mothers with SGA fetuses.

Problem Mannose‐binding lectin (MBL) is a pattern‐recognition receptor that activates complement and modulates inflammation. Homozygosity for the most common allele of the MBL2 gene that is associated with high MBL serum concentrations is more prevalent among patients with pre‐eclampsia. The objective of this study was to determine maternal plasma MBL concentrations in normal pregnant women and patients with pre‐eclampsia. Method of study This cross‐sectional study included normal pregnant women ( n = 187) and patients with pre‐eclampsia ( n = 99). Maternal plasma MBL concentrations were determined by ELISA. Results Women with pre‐eclampsia had a higher median maternal plasma MBL concentration than normal pregnant women. MBL concentration distribution curves were three‐modal, the subintervals in normal pregnancy were low (<143.7), intermediate (143.7–1898.9) and high (>1898.9 ng/mL). The proportion of normal pregnant women was larger in the low subinterval, while the proportion of patients with pre‐eclampsia was larger in the high subinterval ( P = 0.02). Normal pregnant women in the high subinterval had a larger rate of placental underperfusion than those in the low and intermediate subintervals ( P = 0.02). Conclusions The median maternal plasma MBL concentration is elevated in patients with pre‐eclampsia and a larger proportion of these patients are in the high subinterval than normal pregnant women, suggesting that this component of the innate immune system is involved in the mechanisms of disease in pre‐eclampsia.

Objectives To determine the clinical significance of the presence of amniotic fluid (AF) 'sludge' among asymptomatic patients at high risk for spontaneous preterm delivery.Methods This retrospective case-control study included 281 patients with (n = 66) or without (n = 215) AF 'sludge', who underwent transvaginal ultrasound examination between 13 and 29 completed weeks of gestation. Patients with threatened preterm labor, multiple gestation, fetal anomalies, placenta previa or uterine contractions were excluded.Results The prevalence of AF 'sludge' in the study population was 23.5% (66/281). The rates of spontaneous preterm delivery at < 28 weeks, < 32 weeks, < 35 weeks and < 37 weeks of gestation were 14.7% (29/197), 21.3% (46/216), 28.7% (62/216) and 42.1% (91/216), respectively. Patients with 'sludge' had: (1) a higher rate of spontaneous preterm delivery at < 28 weeks (46.5% (20/43) vs. 5.8% (9/154); P < 0.001), < 32 weeks (55.6% (25/45) vs. 12.3% (21/171); P < 0.001) and < 35 weeks (62.2% (28/45) vs. 19.9% (34/171); P < 0.001); (2) a higher frequency of clinical chorioamnionitis (15.2% (10/66) vs. 5.1% (11/215); P = 0.007), histologic chorioamnionitis (61.5% (40/65) vs. 28% (54/193); P < 0.001) and funisitis (32.3% (21/65) vs. 19.2% (37/193); P = 0.03); (3) a higher frequency of preterm prelabor rupture of membranes (PROM) (39.4% (26/66) vs. 13.5% (29/215); P < 0.001), lower gestational age at preterm PROM (median 24.7 (interquartile range (IQR), 22.3-28.1) weeks vs. 32.3 (IQR, 27.7-34.8) weeks; P < 0.001); and (4) shorter median ultrasound-to-delivery interval ('sludge' positive 127 days (95% CI, 120-134 days) vs. 'sludge' negative 161 days (95% CI, 153-169 days); P < 0.001) and ultrasound-to-preterm PROM interval ('sludge' positive 23 days (95% CI, 7-39 days) vs. 'sludge' negative 57 days (95% CI, 38-77 days); P = 0.003) than those without 'sludge'. AF 'sludge' was an independent explanatory variable for the occurrence of spontaneous preterm delivery at < 28 weeks, < 32 weeks and < 35 weeks, preterm PROM, microbial invasion of the amniotic cavity (MIAC) and histologic chorioamnionitis. Moreover, the combination of a cervical length < 25 mm and 'sludge' conferred an odds ratio of 14.8 and 9.9 for spontaneous preterm delivery at < 28 weeks and < 32 weeks, respectively.Conclusions AF 'sludge' is an independent risk factor for spontaneous preterm delivery, preterm PROM, MIAC and histologic chorioamnionitis in asymptomatic patients at high risk for spontaneous preterm delivery. Furthermore, the combination of 'sludge' and a short cervix confers a higher risk for spontaneous preterm delivery at < 28 weeks and < 32 weeks than a short cervix alone. Copyright (C) 2007 ISUOG. Published by John Wiley & Sons, Ltd.

The presence of amniotic fluid (AF) ‘sludge’ is a powerful predictor of intra-amniotic infection, spontaneous preterm delivery and histological chorioamnionitis in both symptomatic and asymptomatic patients. The objective of this study was to determine the clinical significance of the presence of AF ‘sludge’ among patients with a cervical cerclage. This retrospective case–control study included 76 patients with cervical cerclage; 40 had AF ‘sludge’ and 36 did not. Patients with threatened preterm labor, multiple gestation, fetal anomalies, placenta previa and uterine contractions were excluded. The median gestational age at delivery was significantly lower among patients with cerclage and AF ‘sludge’ than among those without AF ‘sludge’ (28.7 (range, 22–39.7) weeks vs. 38 (range, 18.7–40.1) weeks, P = 0.02). Patients with cervical cerclage and AF ‘sludge’ had higher rates of spontaneous preterm delivery at < 28 weeks (50% (9/18) vs. 10.5% (2/19), P = 0.009), < 32 weeks (66.7% (12/18) vs. 15.8% (3/19), P = 0.002) and < 37 weeks (66.7% (12/18) vs. 31.6% (6/19), P = 0.03), preterm PROM (50% (16/32) vs. 25% (8/32), P = 0.04), and histological chorioamnionitis (60% (21/35) vs. 33.3% (11/33), P = 0.03) than patients without ‘sludge’. Amniotic fluid ‘sludge’ in patients with a cervical cerclage is a risk factor for lower gestational age at delivery, preterm PROM, histological chorioamnionitis, and spontaneous preterm delivery at < 28 weeks and < 32 weeks.

OBJECTIVE: An imbalanced chronic blood flow between the donor and recipient twin through placental vascular anastomoses is the accepted pathophysiology of twin-to-twin transfusion syndrome (TTTS). Vascular endothelial growth factor receptor-1 (VEGFR-1) mRNA is overexpressed only in the syncytiotrophoblast of the donor twin in some cases of TTTS. This study was conducted to determine maternal plasma concentrations of placental growth factor (PIGF), soluble VEGFR-1, and soluble endoglin (s-Eng) in monochorionic-diamniotic pregnancies with and without TTTS.STUDY DESIGN: This case-control study included monochorionic-diamniotic pregnancies between 16-26 weeks with and without TTTS. Maternal plasma concentrations of PlGF, sVEGFR-1, and s-Eng were determined with ELISA. A P value <.05 was considered statistically significant.RESULTS: Patients with TTTS had higher median plasma concentrations of s-Eng (14.8 ng/mL vs 7.8 ng/mL; P <.001) and sVEGFR-1 (6383.1 pg/mL vs 3220.1 pg/mL; P <.001]; and lower median plasma concentrations of PlGF (115.5 pg/mL vs 359.3 pg/mL; P =.002) than those without TTTS.CONCLUSION: We propose that an antiangiogenic state may be present in some cases of TTTS.

OBJECTIVE:A sonographically short cervix is a powerful predictor of spontaneous preterm delivery. However, the etiology and optimal management of a patient with a short cervix in the mid-trimester of pregnancy remain uncertain. Microbial invasion of the amniotic cavity (MIAC) and intra-amniotic inflammation are frequently present in patients with spontaneous preterm labor or acute cervical insufficiency. This study was conducted to determine the rate of MIAC and intra-amniotic inflammation in patients with a cervical length < 25 mm in the mid-trimester.STUDY DESIGN:A retrospective cohort study was conducted of patients referred to our high risk clinic because of a sonographic short cervix or a history of a previous preterm birth. Amniocenteses were performed for the evaluation of MIAC and for karyotype analysis in patients with a short cervix. Fluid was cultured for aerobic and anaerobic bacteria, as well as genital mycoplasmas. Patients with MIAC were treated with antibiotics selected by their physician.RESULTS:Of 152 patients with a short cervix at 14-24 weeks, 57 had amniotic fluid analysis. The prevalence of MIAC was 9% (5/57). Among these patients, the rate of preterm delivery (< 32 weeks) was 40% (2/5). Microorganisms isolated from amniotic fluid included Ureaplasma urealyticum (n=4) and Fusobacterium nucleatum (n=1). Patients with a positive culture for Ureaplasma urealyticum received intravenous Azithromycin. Three patients with Ureaplasma urealyticum had a sterile amniotic fluid culture after treatment, and subsequently delivered at term. The patient with Fusobacterium nucleatum developed clinical chorioamnionitis and was induced.CONCLUSION:(1) Sub-clinical MIAC was detected in 9% of patients with a sonographically short cervix (< 25 mm); and (2) maternal parenteral treatment with antibiotics can eradicate MIAC caused by Ureaplasma urealyticum. This was associated with delivery at term in the three patients whose successful treatment was documented by microbiologic studies.

OBJECTIVE: This study aimed to discover "signature pathways" that characterize biologic processes, based on genes differentially expressed in the uterine cervix before and after spontaneous labor.STUDY DESIGN: The cervical transcriptome was characterized previously from biopsy specimens taken before and after term labor. Pathway analysis was used to study the differentially expressed genes, based on 2 gene-to-pathway annotation databases ( Kyoto Encyclopedia of Genes and Genomes [Kanehisa Laboratories, Kyoto University, Kyoto, Japan] and Metacore software [GeneGo, Inc, St. Joseph, MI]). Overrepresented and highly impacted pathways and connectivity nodes were identified.RESULTS: Fifty-two pathways in the Metacore database were enriched significantly in differentially expressed genes. Three of the top 5 pathways were known to be involved in cervical remodeling. Two novel pathways were plasmin signaling and plasminogen activator urokinase signaling. The same analysis with the Kyoto Encyclopedia of Genes and Genomes database identified 4 significant pathways that the impact analysis confirmed. Multiple nodes that provide connectivity within the plasmin and plasminogen activator urokinase signaling pathways were identified.CONCLUSION: Three strategies for pathway analysis were consistent in their identification of novel, unexpected, and expected pathways, which suggests that this approach is both valid and effective for the elucidation of biologic mechanisms that are involved in cervical dilation and remodeling.

WOMEN WITH GESTATIONAL DIABETES JOSE DUNCAN, JERRIE REFUERZO, NATALIA CAMACHO, JYOTHI NICHANAMETLA, SEAN BLACKWELL, ROBERT SOKOL, YORAM SOROKIN, Wayne State University, Obstetrics and Gynecology, Detroit, Michigan, Wayne State University, Obstetrics & Gynecology, Detroit, Michigan, Wayne State University, Obstetrics/Gynecology, Detroit, Michigan, Wayne State University, Ob/Gyn/Maternal Fetal Med, Detroit, Michigan OBJECTIVE: Glyburide has been shown to be as effective as insulin for the treatment of gestational diabetes (GDM). The objective of this study is to determine whether glyburide results in similar delivery outcomes compared to insulin in morbidly obese women with GDM. STUDY DESIGN: A retrospective chart review was performed including women with GDM requiring medical therapy from January 2002 to December 2004. Women with multiple gestations and chromosomal/structural defects were excluded. Morbid obesity was defined as a body mass index (BMI) O 40 kg/m. Women were divided into morbidly obese and non-morbidly obese groups. Delivery outcomes were then compared between women on glyburide therapy versus insulin. RESULTS: There were 90 women who delivered with GDM requiring medical therapy, 28.9% (n=26) were morbidly obese and 71.1% (n=54) were not. Glyburide was given to 34.6% (n=9) of morbidly obese women and to 35.2% (n=19) of non-morbidly obese women. There was no difference between maternal age, race, gestational age at delivery, pre-eclampsia, rates of labor induction or smoking history between women treated with glyburide compared to insulin. In morbidly obese women, glyburide had similar rates of macrosomia (0% vs 23.5%, p=0.159) and cesarean section (55.6% vs. 35.3%, p=0.281) compared to insulin. In the non-morbidly obese women, glyburide significantly reduced the rates of macrosomia (0% vs. 22.9%, p=0.023) and cesarean section (10.4% vs. 51.4%, p=0.003). CONCLUSION: While glyburide has similar delivery outcomes compared to insulin in morbidly obese women with GDM, such therapy appears most effective in reducing the rates of macrosomia and cesarean section in women who are not morbidly obese.