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ABSTRACT: PROBLEM: Pre-eclampsia (PE), a pregnancy complication of unknown etiology, is a major cause of maternal and fetal mortality and morbidity. Previous studies have described placental genes that are up-regulated in expression in PE, but few studies have addressed placental gene suppression in this syndrome. METHOD OF STUDY: Gene profiling and quantitative reverse transcription PCR (qRTPCR) analyses were used to identify genes down-regulated in placentas from women with severe preterm PE compared with gestational age-matched normotensive controls with spontaneous preterm birth (sPTB). Western blotting and immunohistochemistry were used to evaluate levels and patterns of cell type-specific protein expression in PE and sPTB group placentas. RESULTS: Levels of macrophage marker [folate receptor (FR)-β, CD163, and CD68] mRNA and FR-β protein were significantly down-regulated in PE group placentas compared with the sPTB group. Numbers of Hofbauer cells (HBCs, fetal macrophages) and FR-β protein in these cells were reduced in PE group placentas. CONCLUSION: Severe PE is associated with decreased placental expression of FR-β and a reduction in the number of HBCs. Reduced placental macrophage function is likely to play a key role in the pathophysiology of PE.
American Journal Of Reproductive Immunology 03/2013; · 2.17 Impact Factor
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Nadia Falah,
Jude McElroy,
Victoria Snegovskikh,
Charles J Lockwood, Errol Norwitz,
Jeffey C Murray,
Edward Kuczynski,
Ramkumar Menon,
Kari Teramo,
Louis J Muglia,
Thomas Morgan
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ABSTRACT: Preterm birth (PTB) is the leading cause of infant mortality. PTB pathophysiology overlaps with those of adult cardiovascular, immune and metabolic disorders (CIMD), with mechanisms including inflammation, immunotolerance, thrombosis, and nutrient metabolism. Whereas many genetic factors for CIMD have been identified, progress in PTB has lagged. We hypothesized that highly validated genetic risk factors for CIMD may also be associated with PTB. We conducted case-control study of four female cohorts with spontaneous PTB (n = 673) versus term (n = 1119). Of 35 SNPs genotyped, there were 13 statistically significant associations (P < 0.05), which were more than expected (binomial test; P = 0.02). In US White (307 cases/342 controls), the G allele of HLA-DQA1 (A/G) rs9272346 was protective for PTB in the initial discovery cohort (P = 0.02; OR = 0.65; 95 % CI 0.46, 0.94). This protective association replicated (P = 0.02; OR = 0.85; 95 % CI 0.75, 0.97) nominally in the Danish Cohort (883 cases, 959 controls), but lost significance upon multiple testing correction. We observed more statistically significant associations than expected, suggesting that chance is an unlikely explanation for one or more of the associations. Particularly, a protective association of the G allele of HLA-DQA1 was found in two independent cohorts, and in previous studies, this same allele was found to protect against type-1-diabetes (meta-analysis P value 5.52 × 10(-219)). Previous investigations have implicated HLA phenotypic variation in recurrent fetal loss and in chronic chorioamnionitis. Given the limited sample size in his study, we suggest larger studies to further investigate possible HLA genetic involvement in PTB.
Human Genetics 09/2012; · 5.07 Impact Factor
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ABSTRACT: The purpose of this study was to investigate whether poor perinatal outcomes are more common in twins with abnormal umbilical artery Doppler velocimetric findings than in their siblings with normal findings.
A matched-pair cohort analysis of twin pregnancies with discordant umbilical artery Doppler velocimetric findings (one normal and one abnormal) was performed. Both severely abnormal findings (defined as absent or reversed flow in one twin; n = 23) and mildly abnormal findings (defined as an elevated systolic to diastolic ratio in one twin; n = 28) were included. The matched twins provided a gestational age-and demographically matched comparison group. Outcomes measured included intrauterine fetal death, oligohydramnios, intrauterine growth restriction, and neonatal outcomes (birth weight, Apgar scores, intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis). Associations between abnormal Doppler velocimetric findings and perinatal outcomes were estimated using matched logistic regression analysis.
Among this cohort of twin pregnancies with discordant umbilical artery Doppler velocimetric findings, oligohydramnios and intrauterine growth restriction were more frequent in twin fetuses with abnormal findings. Adverse neonatal outcomes were high in both groups (57% among those with normal findings and 49% among those with abnormal findings) because of the overwhelming contribution of preterm delivery (mean gestational age at delivery, 33.3 weeks) but were not significantly different between those fetuses with abnormal findings compared to their cotwins with normal findings.
Our results do not show an association between abnormal umbilical artery Doppler velocimetric findings and short-term adverse neonatal outcomes.
Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 11/2011; 30(11):1561-5. · 1.25 Impact Factor
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ABSTRACT: Placenta accreta is one of the leading causes of peripartum hemorrhage. The goal of this article is to review anesthetic management of parturients with placenta accreta and to examine a modern approach to massive peripartum hemorrhage.
The incidence of placenta accreta is rising in parallel with the increased rate of cesarean delivery. If accreta is diagnosed or suspected preoperatively, anesthetic management can be optimized. Even with the best possible management, the blood loss associated with placenta accreta can resemble that of a major trauma. The use of Damage Control Resuscitation strategies to guide transfusion may improve morbidity and mortality.
Careful planning and close communication are essential between anesthesiology, obstetric, interventional radiology, gynecologic oncology, blood bank, and specialized surgical teams when taking care of a patient with placenta accreta.
Current opinion in anaesthesiology 06/2011; 24(3):274-81.
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ABSTRACT: PROBLEM Placental villus macrophages (i.e., Hofbauer cells, HBCs) were identified more than 100 years ago. Alterations in their numbers and characteristics are associated with several complications of pregnancy. Although HBCs have previously been isolated and cultured, there is no consensus methodology to obtain these cells with high yield and purity for in vitro studies. METHOD OF STUDY Hofbauer cells were isolated from human term placentas using protocols in which cytotrophoblasts (CTs) and fibroblasts (FIBs), other major villous cell types, were isolated in parallel. Enzymatic digestion, Percoll gradients, and immunoselection were used to isolate the three cell types. Purity was assessed by morphology, flow cytometry, and phagocytosis assays. RESULTS Hofbauer cells were isolated with 98-99% purity and a yield of 130-200 × 10(6) cells/80-100 g of tissue. HBCs exhibited a pleiomorphic and vacuolated appearance for at least 5 days in culture medium with and without serum. High levels of phagocytosis in HBCs, but not in CTs or FIBs, confirmed macrophage function in HBCs. Phagocytotic activity was maintained across several days in culture. CONCLUSION Hofbauer cells were isolated from term placenta with high yield and purity using protocols in which CTs and FIBs were also obtained. This methodology will foster future studies that examine the role of HBCs in regulating villus function.
American Journal Of Reproductive Immunology 05/2011; 66(4):336-48. · 2.17 Impact Factor
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Jevon Plunkett,
Scott Doniger,
Guilherme Orabona,
Thomas Morgan,
Ritva Haataja,
Mikko Hallman,
Hilkka Puttonen,
Ramkumar Menon,
Edward Kuczynski, Errol Norwitz, [......],
Vineta Fellman,
Emily A DeFranco,
Bimal P Chaudhari,
Tracy L McGregor,
Jude J McElroy,
Matthew T Oetjens,
Kari Teramo,
Ingrid Borecki,
Justin Fay,
Louis Muglia
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ABSTRACT: Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.
PLoS Genetics 04/2011; 7(4):e1001365. · 8.69 Impact Factor
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ABSTRACT: This study sought to identify women's concerns regarding breastfeeding during the prenatal period and determine whether women thought that health care providers addressed these concerns.
A structured interview with both open-ended and closed-ended questions addressing the study objectives was administered to a cross-sectional sample of 130 English-speaking or Spanish-speaking postpartum women at Yale-New Haven Hospital.
When asked an open-ended question regarding whether they had concerns about breastfeeding while making their decisions about feeding their infants, 81.5% of women identified at least 1 concern. Of these women, only 25.4% reported that this concern was addressed by the provider during prenatal care. When prompted with 8 common concerns regarding breastfeeding during the prenatal period, 95.4% of women identified at least 1 of these preidentified concerns. Only 17.4% of women who identified any of these 8 concerns reported that the concerns had been discussed with a provider.
Women's recall of prenatal health care discussions strongly suggests that providers are not adequately addressing women's concerns about breastfeeding.
Journal of midwifery & women's health 01/2011; 56(1):2-7. · 1.13 Impact Factor
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Jevon Plunkett,
Scott Doniger,
Thomas Morgan,
Ritva Haataja,
Mikko Hallman,
Hilkka Puttonen,
Ramkumar Menon,
Edward Kuczynski, Errol Norwitz,
Victoria Snegovskikh, [......],
Emily DeFranco,
Bimal Chaudhari,
John Oates,
Olivier Boutaud,
Tracy McGregor,
Jude McElroy,
Kari Teramo,
Ingrid Borecki,
Justin Fay,
Louis Muglia
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ABSTRACT: Abstract Background The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance. Methods We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers. Results Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity. Conclusions Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.
BMC Medical Genomics. 01/2010;
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Jevon Plunkett,
Scott Doniger,
Thomas Morgan,
Ritva Haataja,
Mikko Hallman,
Hilkka Puttonen,
Ramkumar Menon,
Edward Kuczynski, Errol Norwitz,
Victoria Snegovskikh, [......],
Emily A DeFranco,
Bimal P Chaudhari,
John Oates,
Olivier Boutaud,
Tracy L McGregor,
Jude J McElroy,
Kari Teramo,
Ingrid Borecki,
Justin C Fay,
Louis J Muglia
[show abstract]
[hide abstract]
ABSTRACT: The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance.
We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers.
Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity.
Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.
BMC Medical Genomics 01/2010; 3:62. · 3.69 Impact Factor
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ABSTRACT: Cesarean scar ectopic pregnancy is becoming increasingly common at tertiary care hospitals around the world. It is a condition in which the embryo implants within the myometrium at the site of a previous cesarean hysterotomy, and it can occur in women with only one prior cesarean delivery. We present four cases of cesarean scar ectopic pregnancy diagnosed within a 6-month period between 2007 and 2008. Their initial presentations and management are discussed, followed by a review of the published literature summarizing both diagnostic and management recommendations.
American Journal of Perinatology 07/2009; 27(2):111-20. · 1.32 Impact Factor
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ABSTRACT: Postterm pregnancy is defined as one which has progressed to 42 0/7 weeks or beyond. The most common reason to be diagnosed with a postterm pregnancy is inaccurate pregnancy dating, but it is also associated with obesity, nulliparity, and a prior history of postterm pregnancy. The rate of postterm pregnancy appears to be decreasing whether due to improved pregnancy dating or an increase in induction of labor. Postterm pregnancy is associated with both maternal and neonatal morbidity and fetal and neonatal mortality; similarly pregnancies beyond 41 weeks' gestation are associated with increases in these perinatal complications. Prevention of postterm pregnancies may include stripping or sweeping the membranes and unprotected coitus. Management of such pregnancies may include induction of labor and fetal antenatal monitoring. Individual patient management should involve careful counseling regarding the risks and benefits of each of the components of care. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to recall the increasing risks of poor outcomes associated with prolonged pregnancy, demonstrate knowledge regarding gestational dating and use of cervical ripening agents in their care of pregnant women, and use evidence-based information when counseling their term patients regarding postterm pregnancy management.
Obstetrical & gynecological survey 11/2008; 63(11):715-24. · 3.10 Impact Factor
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ABSTRACT: We sought to define the risk of neonatal respiratory distress syndrome (RDS) as a function of both lecithin/sphingomyelin (L/S) ratio and gestational age. Amniotic fluid L/S ratio data were collected from consecutive women undergoing amniocentesis for fetal lung maturity at Yale-New Haven Hospital from January 1998 to December 2004. Women were included in the study if they delivered a live-born, singleton, nonanomalous infant within 72 hours of amniocentesis. The probability of RDS was modeled using multivariate logistic regression with L/S ratio and gestational age as predictors. A total of 210 mother-neonate pairs (8 RDS, 202 non-RDS) met criteria for analysis. Both gestational age and L/S ratio were independent predictors of RDS. A probability of RDS of 3% or less was noted at an L/S ratio cutoff of > or = 3.4 at 34 weeks, > or = 2.6 at 36 weeks, > or = 1.6 at 38 weeks, and > or = 1.2 at term. Under 34 weeks of gestation, the prevalence of RDS was so high that a probability of 3% or less was not observed by this model. These data describe a means of stratifying the probability of neonatal RDS using both gestational age and the L/S ratio and may aid in clinical decision making concerning the timing of delivery.
American Journal of Perinatology 09/2008; 25(8):473-80. · 1.32 Impact Factor
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ABSTRACT: We sought to determine if advanced maternal age (AMA) is a risk factor for intrauterine fetal demise (IUFD). We used a U.S. Centers for Disease Control and Prevention database and analyzed outcomes in women 15 to 44 years of age with term singleton gestations. Cox proportional hazards models and Cochran-Mantel-Haenszel tests were used. Results were controlled for maternal race and smoking. After excluding congenital anomalies and medical complications, 6,239,399 singleton term deliveries were identified. When compared with women 25 to 29 years of age, the risk of IUFD increased with advancing age: 30 to 34 years, odds ratio [OR] = 1.24 (95% confidence interval [CI], 1.13 to 1.36); 35 to 39 years, OR = 1.45 (95% CI, 1.21 to 1.74), and 40 to 44 years, OR = 3.04 (95% CI, 1.58 to 5.86). The risk of IUFD for women 40 to 44 years of age at 39 weeks is comparable with that of 42 weeks in those 25 to 29 years of age. We concluded that AMA is an independent predictor of IUFD, and a strategy of antenatal testing in those > or = 40 years of age beginning at 38 weeks may be considered.
American Journal of Perinatology 05/2008; 25(5):301-4. · 1.32 Impact Factor
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Margaret E Samuels-Kalow,
Edmund F Funai,
Catalin Buhimschi, Errol Norwitz,
Mary Perrin,
Ronit Calderon-Margalit,
Lisa Deutsch,
Ora Paltiel,
Yechiel Friedlander,
Orly Manor,
Susan Harlap
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ABSTRACT: Recent studies have shown increased maternal mortality rates after hypertensive disorders of pregnancy (HDP), but the reasons for this increase remain unclear. This study examines the relationship between elevated prepregnancy body mass index (BMI), HDP, and postpregnancy mortality.
Data came from a 1975-1976 subset (n = 13,722 women) of a population-based cohort. Multiple logistic regression was used to examine the risk of HDP by BMI; age-adjusted Cox proportional hazards models were used to examine survival rates.
Overweight (BMI, 25-29.9 kg/m2) and obesity (BMI, > or = 30 kg/m2) were associated with increased HDP (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.40-3.31 and OR, 5.51; 95% CI, 4.15-7.31]) and decreased survival (hazard ratio [HR], 1.42; 95% CI, 1.10-1.83 and HR, 2.43; 95% CI, 1.61-3.68), compared with normal weight (BMI, 18.5-24.9 kg/m2). HDP was significantly associated with increased mortality rates for women who survived > 15 years (HR, 1.94; 95% CI, 1.42-2.67]; HR adjusted for BMI, 1.65; 95% CI, 1.19-2.79]). A greater increase in risk of death after HDP was seen in the overweight women (HR, 1.86; 95% CI, 1.07-3.20) and obese women (HR, 2.90; 95% CI, 1.28-6.58), compared with normal weight women (HR, 1.26; 95% CI, 0.74-2.14).
Elevated prepregnancy BMI is associated with increased risk of HDP, which are in turn is associated with increased long-term maternal mortality rates. This association between HDP and mortality rates increases with elevated prepregnancy BMI.
American journal of obstetrics and gynecology 12/2007; 197(5):490.e1-6. · 3.28 Impact Factor
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ABSTRACT: Nucleated red blood cells (NRBCs) in fetal circulation have been proposed as a marker of chronic hypoxia in fetuses with intrauterine growth restriction (IUGR). We sought to determine the effects of chronic hypoxia, chronic nitric oxide inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME), or both on NRBC counts, erythropoietin levels, and pathologic changes in an animal model of IUGR.
We assigned timed pregnant adult Sprague Dawley rats to the following groups: (1) 21% oxygen + saline solution (n = 7); (2) 21% oxygen + L-NAME (n = 8); (3) 10% oxygen + saline solution (n = 6); and (4) 10% oxygen + L-NAME (n = 6). We inserted osmotic pumps that were prefilled with saline solution or L-NAME subcutaneously on day 17 of gestation. The animals were placed in a Plexiglas hypoxic chamber, which ensured a constant hypoxic environment. The animals were killed on day 21 of gestation before the onset of spontaneous labor. We collected maternal and fetal blood for measurement of NRBC and erythropoietin levels. The results were interpreted in relationship to maternal arterial blood gases and hemoglobin and hematocrit levels. Fetuses were examined for gross abnormalities and histological abnormalities that are characteristic of vascular disruptions by a blind examiner to experimental manipulation.
Nitric oxide inhibition induced IUGR with maximal effect when both L-NAME and hypoxia treatments were combined. Inhibition of nitric oxide synthesis, but not chronic hypoxia, increased the number of fetal NRBCs and generalized hemorrhagic diathesis in utero. These features were aggravated significantly when the treatments were combined. Moreover, chronic hypoxia induced significant maternal metabolic acidosis and increased hematocrit and erythropoietin levels in maternal and fetal blood. Nitric oxide inhibition increased maternal hematocrit levels while decreasing maternal erythropoietin levels without significantly altering the maternal acid-base status. In contrast with chronic hypoxia, nitric oxide inhibition increased fetal NRBCs without affecting erythropoietin levels.
Our findings indicate that the number of NRBCs in fetal circulation does not serve as a specific marker of chronic hypoxia that accompanies IUGR or of elevated erythropoietin levels but are an epiphenomenon that is related to the inhibition of nitric oxide.
American journal of obstetrics and gynecology 06/2007; 196(5):482.e1-8. · 3.28 Impact Factor
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ABSTRACT: The primary placental defect in preeclampsia is shallow trophoblast invasion of the decidua leading to incomplete vascular transformation and inadequate uteroplacental perfusion. Soluble fms-like tyrosine kinase-1 (sFlt-1) seems to interfere with these events by inhibiting local angiogenesis and/or by impeding trophoblast invasion. Preeclampsia is also associated with maternal thrombophilias and decidual hemorrhage, which form thrombin from decidual cell-expressed tissue factor. Although sFlt-1 is highly expressed by trophoblasts, sFlt-1 expression has not been studied in decidual cells, which are the predominant cell type encountered by invading trophoblasts. Here, we demonstrate that isolated decidual cells express sFlt-1 mRNA, suggesting that they can synthesize sFlt-1. Moreover, in first trimester decidual cells, thrombin enhanced sFlt-1 mRNA levels, as measured by quantitative reverse transcriptase-polymerase chain reaction, and levels of secreted sFlt-1 protein, as measured by enzyme-linked immunosorbent assay. The thrombin antagonist hirudin blocked this effect, demonstrating that active thrombin is required. Emphasizing the specificity of the thrombin response, neither interleukin-1beta nor tumor necrosis factor-alpha affected sFlt-1 expression in the decidual cells. In contrast to first trimester decidual cells, thrombin did not affect sFlt-1 levels in cultured term decidual cells. In early pregnancy, thrombin may act as an autocrine/paracrine enhancer of sFlt-1 expression by decidual cells to promote pre-eclampsia by interfering with local vascular transformation.
American Journal Of Pathology 04/2007; 170(4):1398-405. · 4.89 Impact Factor
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ABSTRACT: We hypothesized that nitric oxide (NO) inhibition has synergistic effects with chronic hypoxia in altering maternal serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), vascular endothelial growth factor (VEGF), and placental growth factor (PlGF). We tested our hypothesis in a rodent model of intrauterine growth restriction induced by chronic hypoxia and NO inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME).
Timed pregnant adult Sprague-Dawley rats were assigned to the following groups: (1) 20% (oxygen) O2 + saline (n = 7); (2) 20% O2 + L-NAME (n = 8); (3) 14% O2 + saline (n = 5); (4) 14% O2 + L-NAME (n = 5); (5) 10% O2 + saline (n = 6); and (6) 10% O2 + L-NAME (n = 6). Seven nulliparous females served as nonpregnant controls. L-NAME (50 mg/rat/day) or saline was administered via subcutaneous osmotic pumps, inserted on day 17 of gestation. A hypoxic chamber was used to assure mild (14% O2) or severe (10% O2) hypoxic environment after surgical placement of the minipumps and until the animals were killed on day 21 of gestation before the onset of labor. Maternal blood was collected preceding death. Free serum levels of VEGF, PlGF, and sFlt-1 were measured by highly specific immunoassays. Two composite indices were calculated (sFV: log [(sFlt-1)/VEGF] and sFP: log [(sFlt-1)/PlGF] and compared among groups.
Fetal growth restriction was induced by both severe hypoxia (10% O2) and L-NAME infusion (2-way analysis of variance, P = .02 O2 levels, P < .001 L-NAME), whereas their combination proved to be the most damaging (P < .001). Pregnancy was characterized by higher maternal serum concentrations of VEGF (P < .001) and PlGF (P < .001), but lower levels of sFlt-1 (P = .037) compared with nonpregnant controls. Serum VEGF levels were not altered by either hypoxia or L-NAME infusion (P = .348 O2 levels, P = .205 L-NAME). In contrast, L-NAME significantly increased sFlt-1 serum levels independent of O2 levels (P = .032, L-NAME treatment, P = .991 O2 levels). Chronic hypoxia significantly decreases the circulating levels of PlGF (P < .001) independent of L-NAME treatment. The sFV ratio was neither altered by hypoxia nor by L-NAME infusion. In contrast, the sFP ratio was significantly increased by both L-NAME (P < .001) and severe hypoxia (P < .001), but the effect was not synergistic (P = .655).
Chronic NO inhibition as well as hypoxia induce fetal growth restriction and significantly change maternal circulating levels of sFlt-1 and PlGF, but not of VEGF. The primary effect of chronic hypoxia is in decreasing circulating levels of PlGF that contrasts with that of NO inhibition, which selectively increases sFlt-1 levels. Their effect is thus not synergistic, suggesting independent pathways.
American journal of obstetrics and gynecology 02/2007; 196(1):72.e1-6. · 3.28 Impact Factor
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JAMA The Journal of the American Medical Association 12/2004; 292(19):2338; author reply 2338-9. · 30.03 Impact Factor
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ABSTRACT: The relationship between a single nucleotide polymorphism (TLR4 896 A > G) in the toll-like receptor-4 (TLR4) gene, qualitative and quantitative changes in vaginal micro-flora and vaginal interleukin (IL)-1beta and IL-1 receptor antagonist (IL-1ra) concentrations in pregnant women were evaluated.
Qualitative and quantitative microbial methods were used to characterize vaginal micro-flora of 238 women at 18-22 weeks gestation. Polymerase chain reaction was used to determine TLR4 genotype. IL-1beta and IL-1ra concentrations in vaginal lavage samples were measured by ELISA.
The TLR4 variant was identified in 10.3% of women. Carriage of this variant was associated with a median increase in vaginal pH (P = 0.05), a greater than 10-fold increase in vaginal Gardnerella vaginalis levels (P < 0.0001) and a 10-fold increase in the vaginal concentration of three species of anaerobic Gram-negative rods, Prevotella, Bacteroides, and Porphyromonas (P = 0.08 ). Colonization with G. vaginalis and/or the anaerobic Gram-negative rods resulted in elevated vaginal IL-1 (P = 0.01) and IL-1ra (P < 0.0002) concentrations in women who were TLR4 896A homozygotes, but not in TLR4 896G carriers.
The TLR4 896 A > G polymorphism contributes to inter-individual differences in the vaginal immune defense against G. vaginalis and anaerobic Gram-negative rods.
European Journal of Obstetrics & Gynecology and Reproductive Biology 11/2004; 116(2):152-6. · 1.97 Impact Factor
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ABSTRACT: Symptomatic maternal diaphragmatic hernia in a pregnant woman is a surgical emergency associated with high morbidity and mortality both for her and her fetus. Such patients are most commonly managed with immediate cesarean delivery combined with hernia repair.
A woman presented at 29 weeks' gestation with symptoms of bowel obstruction due to herniation of viscera through a previously undiagnosed congenital diaphragmatic hernia of Bochdalek, and she was stabilized. Antenatal corticosteroids were administered to facilitate fetal maturity. The hernia was repaired 10 days after her presentation because of evidence of incarceration. Labor was induced at 39 weeks' gestation, and a healthy infant was delivered vaginally.
Expectant management and vaginal delivery after antepartum repair of congenital diaphragmatic hernia in the mother is a reasonable alternative to immediate cesarean delivery.
Obstetrics and Gynecology 12/2003; 102(5 Pt 2):1194-6. · 4.73 Impact Factor
