Azithromycin-based Extended-Spectrum Antibiotic Prophylaxis for Cesarean: Role of Placental Colonization with Genital Ureaplasmas and Mycoplasmas.

OBJECTIVE: To explore whether the effect of azithromycin (AZI) on postcesarean infections varied by the presence/absence of genital mycoplasmataceae placental colonization. STUDY DESIGN: This was a single-center substudy of multicenter double-blind C/SOAP (Cesarean Section Optimal Antibiotic Prophylaxis) trial of women randomized to AZI or placebo (+cefazolin) antibiotic prophylaxis at cesarean. Chorioamnion/placenta specimens were tested for genital mycoplasmataceae colonization by polymerase chain reaction. Primary outcome was a composite of endometritis, wound infection, or other infections up to 6 weeks postpartum. Analysis was intent-to-treat; logistic regression was used to evaluate interactions between treatment assignment (AZI/placebo) and the presence/absence of mycoplasmataceae and to quantify effects of AZI in analyses stratified by the presence/absence of these microorganisms. RESULTS: Specimens from 613 women (303 AZI and 310 placebo) were evaluated. Baseline characteristics were similar between groups, and approximately 1/3 (30.3%) had mycoplasmataceae placental/chorioamnion colonization. There was no evidence of effect modification (p interaction = 0.79) between treatment assignment and the presence/absence of organisms. Stratified analyses showed fewer events in the AZI group in the presence (odds ratio [OR]: 0.42; 95% confidence interval [CI]: 0.17-1.01) and absence (OR: 0.49; 95% CI: 0.24-1) of mycoplasmataceae. Results were similar with endometritis/wound infections and with ureaplasmas/mycoplasmas considered separately. CONCLUSION: The reduction in postcesarean infection with AZI does not vary based on the presence or absence of genital mycoplasmataceae placental colonization.

Impact of Gestational Weight Gain on Perinatal Outcomes in Obese Women.

Objective This study aims to evaluate perinatal outcomes, according to gestational weight gain (GWG) in obese women. Study Design A retrospective cohort of perinatal outcomes in obese women who gained below, within, or above the 2009 Institute of Medicine guidelines and delivered ≥ 36 weeks. Additionally, outcomes, according to the rate of GWG (kg/week; minimal [< 0.16], moderate [0.16-0.49], or excessive [> 0.49]) were compared among women delivering preterm. Results Overall, 5,651 obese women delivered ≥ 36 weeks. GWG above guidelines was associated with increased cesarean section (adjusted odds ratio [aOR]: 1.44, 95% confidence interval [CI]: 1.21-1.72), gestational hypertension (aOR: 1.58, 95% CI: 1.21-2.06), and macrosomia (birth weight ≥ 4,000 g) (aOR: 2.08, 95% CI: 1.62-2.67). GWG below recommendations was associated with less large for gestational age infants (aOR: 0.60, 95% CI: 0.47-0.75). A total of 6,663 women delivered ≥ 20 weeks. Minimal weekly GWG was associated with increased spontaneous preterm birth (aOR: 1.56, 95% CI: 1.23-1.98) and more small for gestational age (SGA) infants (aOR: 1.55, 95% CI: 1.19-2.01). Excessive weekly GWG was associated with increased indicated preterm birth (aOR: 1.61, 95% CI: 1.29-2.01), cesarean section (aOR: 1.39, 95% CI: 1.20-1.61), preeclampsia (aOR: 1.83, 95% CI: 1.49-2.26), neonatal intensive care unit admission (aOR: 1.33, 95% CI: 1.08-1.63), and macrosomia (aOR: 2.40, 95% CI: 1.94-2.96). Conclusions Obese women with excessive GWG had worse outcomes than women with GWG within recommendations. Limited GWG was associated with increased spontaneous preterm birth and SGA infants.

Abdominal Incision Selection for Cesarean Delivery of Women with Class III Obesity.

Objective The objective of this study was to evaluate cesarean outcomes, stratified by abdominal incision type, in women with class III obesity. Study Design We performed a retrospective cohort study of patients with class III obesity undergoing cesarean at our institution from 2010 to 2013 with singletons ≥ 34 weeks. Outcomes were compared between patients with transverse subpannicular and vertical abdominal incisions. The primary outcome was a wound composite (cellulitis, abscess, hematoma, seroma, or dehiscence). Other outcomes included transfusion, vertical hysterotomy, 5-minute Apgar < 7, and umbilical artery pH < 7.10. Results Of 423 patients, 364 had subpannicular transverse, 57 had vertical, and 2 had periumbilical transverse incisions (not analyzed). Although vertical incisions were associated with more wound complications (26.3 vs. 14.8%; p = 0.03), the difference became null after adjustment (adjusted odds ratios [aOR], 1.7; 95% confidence interval [CI], 0.7, 4.1). Vertical incisions were associated with increased risk of vertical hysterotomy (aOR 4.8; 95% CI, 2.2, 10.4), decreased risk of 5-minute Apgar < 7 (aOR, 0.06; 95% CI, 0.004, 0.9), and not statistically significantly associated with transfusion (aOR, 4.2; 95% CI, 0.9, 19.0) or umbilical artery pH < 7.1 (aOR, 0.42; 95% CI, 0.11, 1.7). Conclusions In women with class III obesity cesarean delivery via vertical abdominal incisions is associated with more maternal but less immediate neonatal complications.

Perinatal pharmacokinetics of azithromycin for cesarean prophylaxis.

OBJECTIVE: Postpartum infections are polymicrobial and typically include Ureaplasma, an intracellular microbe that is treated by macrolides such as azithromycin. The aim of this study was to evaluate the perinatal pharmacokinetics of azithromycin after a single preincision dose before cesarean delivery. STUDY DESIGN: Thirty women who underwent scheduled cesarean delivery were assigned randomly to receive 500 mg of intravenous azithromycin that was initiated 15, 30, or 60 minutes before incision and infused over 1 hour. Serial maternal plasma samples were drawn from the end of infusion up to 8 hours after the infusion. Samples of amniotic fluid, umbilical cord blood, placenta, myometrium, and adipose tissue were collected intraoperatively. Breast milk samples were collected 12-48 hours after the infusion in 8 women who were breastfeeding. Azithromycin was quantified with high performance liquid chromatography separation coupled with tandem mass spectrometry detection. Plasma pharmacokinetic parameters were estimated with the use of noncompartmental analysis and compartmental modeling and simulations. RESULTS: The maximum maternal plasma concentration was reached within 1 hour and exceeded the in vitro minimum inhibitory concentration (MIC50) of 250 ng/mL of Ureaplasma spp in all 30 patients. The concentrations were sustained with a half-life of 6.7 hours. The median concentration of azithromycin in adipose tissue was 102 ng/g, which was below the MIC50. The median concentration in myometrium was 402 ng/g, which exceeded the MIC50. Azithromycin was detectable in both the umbilical cord plasma and amniotic fluid after the single preoperative dose. Azithromycin concentrations in breast milk were high and were sustained up to 48 hours after the single dose. Simulations demonstrated accumulation in breast milk after multiple doses. CONCLUSION: A single dose of azithromycin achieves effective plasma and tissue concentrations and is transported rapidly across the placenta. The tissue concentrations that are achieved in the myometrium exceed the MIC50 for Ureaplasma spp.

An economic analysis of prenatal cytogenetic technologies for sonographically detected fetal anomalies.

When congenital anomalies are diagnosed on prenatal ultrasound, the current standard of care is to perform G-banded karyotyping on cultured amniotic cells. Chromosomal microarray (CMA) can detect smaller genomic deletions and duplications than traditional karyotype analysis. CMA is the first-tier test in the postnatal evaluation of children with multiple congenital anomalies. Recent studies have demonstrated the utility of CMA in the prenatal setting and have advocated for widespread implementation of this technology as the preferred test in prenatal diagnosis. However, CMA remains significantly more expensive than karyotype. In this study, we performed an economic analysis of cytogenetic technologies in the prenatal diagnosis of sonographically detected fetal anomalies comparing four strategies: (i) karyotype alone, (ii) CMA alone, (iii) karyotype and CMA, and (iv) karyotype followed by CMA if the karyotype was normal. In a theoretical cohort of 1,000 patients, CMA alone and karyotype followed by CMA if the karyotype was normal identified a similar number of chromosomal abnormalities. In this model, CMA alone was the most cost-effective strategy, although karyotype alone and CMA following a normal karyotype are both acceptable alternatives. This study supports the clinical utility of CMA in the prenatal diagnosis of sonographically detected fetal anomalies.

Delivery timing and cesarean delivery risk in women with mild gestational diabetes mellitus.

OBJECTIVE: The purpose of this study was to evaluate the relationship between gestational age (GA) and induction of labor (IOL) and the rate of cesarean delivery in women with mild gestational diabetes mellitus. STUDY DESIGN: We conducted a secondary analysis of data from a multicenter randomized controlled trial of mild gestational diabetes mellitus treatment. Cesarean delivery rate of women delivering at term (≥37 weeks' gestation) was evaluated by 2 complementary approaches: (1) IOL vs spontaneous labor: women who were induced at each GA compared with those who spontaneously labored at the same GA and (2) IOL vs expectant management: women who delivered after IOL at each GA compared with those who delivered after spontaneous labor at the same GA or subsequently after spontaneous or induced labor (outcome at each week compared with expectant management at that week). Logistic regression adjusted for potential confounders. RESULTS: The overall cesarean delivery rate was 13%. When compared with 39 weeks' gestation (either IOL or spontaneous labor) as the referent, there was no significant difference in the cesarean delivery rate in women who delivered at 37, 38, or 40 weeks' gestation. However, IOL was associated with a 3-fold increase in cesarean delivery rate at 41 weeks' gestation and beyond, as compared with IOL at 39 weeks' gestation. Similarly, there was a 3-fold increase in the cesarean delivery rate in women who were induced when compared with those who were treated expectantly at 40 completed weeks' gestation. CONCLUSION: Induction of labor in women with mild gestational diabetes mellitus does not increase the rate of cesarean delivery at <40 weeks' gestation.

Outcomes of gynecologic oncology patients undergoing gastrografin small bowel follow-through studies.

OBJECTIVE: To characterize the outcomes of gynecologic oncology patients undergoing small bowel follow-throughs (SBFTs) with Gastrografin at our institution. STUDY DESIGN: We identified all gynecologic oncology patients undergoing an SBFT from January 2004 to December 2009. We characterized the SBFT as normal, delayed transit, partial obstruction, or complete obstruction. Patient outcomes were correlated with the SBFT results. RESULTS: Seventy patients underwent 79 SBFT examinations with Gastrografin to evaluate their bowel dysfunction. The overall rate of operative intervention was 23%. A total of 69% of patients with a complete obstruction underwent surgery as compared to 21% of patients with a partial obstruction (p = 0.002). Return of bowel function was significantly longer in patients with complete obstructions as compared to patients with partial obstructions (48 vs. 8 hours, p = 0.006). Length of stay was longest in patients with complete obstructions. CONCLUSION: The majority of patients with a complete obstruction on SBFT will require surgical intervention and have a protracted hospital stay. Patients with delayed transit or a partial obstruction on SBFT usually will have resolution of their bowel dysfunction with conservative management.

Assessment of risk factors for 30-day hospital readmission after surgical cytoreduction in epithelial ovarian carcinoma.

OBJECTIVE: To evaluate factors that place epithelial ovarian cancer (EOC) patients at increased risk for hospital readmission. METHODS: A retrospective review of patients diagnosed with EOC undergoing surgical cytoreduction at the University of Alabama at Birmingham from 2001 to 2008 was performed. Patients who required readmission were identified. Demographic data, comorbidities, surgical data including bowel resections, and hospital length of stay were evaluated. RESULTS: A total of 207 patients were identified. The mean age at diagnosis was 64 years (range, 32-89 years), 58% had optimal debulking (n=120), and the mean number of comorbidities was 1.3 (range, 0-6). Readmission within 30 days of discharge occurred in 33 (16%) of 207 patients. The readmission group had a statistically higher number of comorbidities (1.75 vs 1.01, P=0.025). The most common reasons for readmission were small bowel obstruction/ileus, wound complications, and thromboembolic events. CONCLUSIONS: The most common reason for readmission after cytoreductive surgery for EOC is small bowel obstruction/ileus. Studies assessing postoperative disease management programs including nursing telephone follow-up, administration of outpatient intravenous fluids, and continuation of antithrombotic agents may offer opportunities to reduce readmissions.

Semaphorin 3B is a 1,25-Dihydroxyvitamin D3-induced gene in osteoblasts that promotes osteoclastogenesis and induces osteopenia in mice.

The vitamin D endocrine system is important for skeletal homeostasis. 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] impacts bone indirectly by promoting intestinal absorption of calcium and phosphate and directly by acting on osteoblasts and osteoclasts. Despite the direct actions of 1,25(OH)(2)D(3) in bone, relatively little is known of the mechanisms or target genes that are regulated by 1,25(OH)(2)D(3) in skeletal cells. Here, we identify semaphorin 3B (SEMA3B) as a 1,25(OH)(2)D(3)-stimulated gene in osteoblastic cells. Northern analysis revealed strong induction of SEMA3B mRNA by 1,25(OH)(2)D(3) in MG-63, ST-2, MC3T3, and primary osteoblastic cells. Moreover, differentiation of these osteogenic cells enhanced SEMA3B gene expression. Biological effects of SEMA3B in the skeletal system have not been reported. Here, we show that osteoblast-derived SEMA3B alters global skeletal homeostasis in intact animals and osteoblast function in cell culture. Osteoblast-targeted expression of SEMA3B in mice resulted in reduced bone mineral density and aberrant trabecular structure compared with nontransgenic littermates. Histomorphometry studies indicated that this was likely due to increased osteoclast numbers and activity. Indeed, primary osteoblasts obtained from SEMA3B transgenic mice stimulated osteoclastogenesis to a greater extent than nontransgenic osteoblasts. This study establishes that SEMA3B is a 1,25(OH)(2)D(3)-induced gene in osteoblasts and that osteoblast-derived SEMA3B impacts skeletal biology in vitro and in vivo. Collectively, these studies support a putative role for SEMA3B as an osteoblast protein that regulates bone mass and skeletal homeostasis.

Functional cooperation between CCAAT/enhancer-binding proteins and the vitamin D receptor in regulation of 25-hydroxyvitamin D3 24-hydroxylase.

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] induces the synthesis of 25-hydroxyvitamin D(3) 24-hydroxylase [24(OH)ase], an enzyme involved in its catabolism, thereby regulating its own metabolism. Here we demonstrate that CCAAT enhancer binding protein beta (C/EBPbeta) is induced by 1,25(OH)(2)D(3) in kidney and in osteoblastic cells and is a potent enhancer of vitamin D receptor (VDR)-mediated 24(OH)ase transcription. Transfection studies indicate that 1,25(OH)(2)D(3) induction of 24(OH)ase transcription is enhanced a maximum of 10-fold by C/EBPbeta. Suppression of 1,25(OH)(2)D(3)-induced 24(OH)ase transcription was observed with dominant negative C/EBP or osteoblastic cells from C/EBPbeta(-/-) mice. A C/EBP site was identified at positions -395 to -388 (-395/-388) in the rat 24(OH)ase promoter. Mutation of this site inhibited C/EBPbeta binding and markedly attenuated the transcriptional response to C/EBPbeta. We also report the cooperation of CBP/p300 with C/EBPbeta in regulating VDR-mediated 24(OH)ase transcription. We found that not only 1,25(OH)(2)D(3) but also parathyroid hormone (PTH) can induce C/EBPbeta expression in osteoblastic cells. PTH potentiated the induction of C/EBPbeta and 24(OH)ase expression in response to 1,25(OH)(2)D(3) in osteoblastic cells. Data with the human VDR promoter (which contains two putative C/EBP sites) indicate a role for C/EBPbeta in the protein kinase A-mediated induction of VDR transcription. From this study a fundamental role has been established for the first time for cooperative effects and cross talk between the C/EBP family of transcription factors and VDR in 1,25(OH)(2)D(3)-induced transcription. These findings also indicate a novel role for C/EBPbeta in the cross talk between PTH and 1,25(OH)(2)D(3) that involves the regulation of VDR transcription.

Hypertensive Disorders in Pregnancy.

Hypertensive disorders of pregnancy are a heterogeneous group of conditions that include chronic hypertension, gestational hypertension, preeclampsia, and preeclampsia superimposed on chronic hypertension. These disorders account for a significant proportion of perinatal morbidity and mortality nearly 10% of all maternal deaths in the United States. Given the substantial health burden of hypertensive disorders in pregnancy, there is increasing interest in optimizing management of these conditions. This article summarizes the diagnosis and management of each of the disorders in the spectrum of hypertension in pregnancy and highlights recent updates in the field.

The pleiotropic effects of excessive luteinizing hormone secretion in transgenic mice.

Luteinizing hormone (LH) is member of the glycoprotein hormone family of gonadotropins, which also includes the highly related human chorionic gonadotropin and follicle-stimulating hormone. The necessity of these factors for sustaining human fertility has been known for decades. In addition, elevated serum levels of LH have been associated with polycystic ovarian syndrome, suggesting that the appropriate balance of LH is critical for maintaining reproductive function. To dissect the biological consequences of aberrant LH signaling in vivo, several genetically engineered mouse models have been developed that overexpress LH or have increased LH signaling. These models underscore the importance of tightly regulated LH levels for normal reproductive function, and reveal novel roles for LH and gonadal hormones in tumorigenesis of multiple tissues, including the ovary, mammary gland, and pituitary. Thus, mice with altered LH signaling provide valuable tools in understanding normal reproduction and various pathological conditions.

The 1,25(OH)2D3-regulated transcription factor MN1 stimulates vitamin D receptor-mediated transcription and inhibits osteoblastic cell proliferation.

The vitamin D endocrine system is essential for maintaining mineral ion homeostasis and preserving bone density. The most bioactive form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] elicits its effects by binding to the vitamin D receptor (VDR) and regulating the transcription of target genes. In osteoblasts, the bone-forming cells of the skeleton, 1,25-(OH)2D3 regulates cell proliferation, differentiation, and mineralization of the extracellular matrix. Despite these well-characterized biological functions, relatively few 1,25-(OH)2D3 target genes have been described in osteoblasts. In this study, we characterize the regulation and function of MN1, a novel 1,25-(OH)2D3-induced gene in osteoblastic cells. MN1 is a nuclear protein first identified as a gene disrupted in some meningiomas and leukemias. Our studies demonstrate that MN1 preferentially stimulates VDR-mediated transcription through its ligand-binding domain and synergizes with the steroid receptor coactivator family of coactivators. Furthermore, forced expression of MN1 in osteoblastic cells results in a profound decrease in cell proliferation by slowing S-phase entry, suggesting that MN1 is an antiproliferative factor that may mediate 1,25-(OH)2D3-dependent inhibition of cell growth. Collectively, these data indicate that MN1 is a 1,25-(OH)2D3-induced VDR coactivator that also may have critical roles in modulating osteoblast proliferation.

Vitamin D: more than a "bone-a-fide" hormone.

The vitamin D endocrine system is critical for the proper development and maintenance of mineral ion homeostasis and skeletal integrity. Beyond these classical roles, recent evidence suggests that the bioactive metabolite of vitamin D, 1,25-dihydroxyvitamin D3, functions in diverse physiological processes, such as hair follicle cycling, blood pressure regulation, and mammary gland development. This minireview explores the current progress in unraveling the complexities of the vitamin D endocrine system by focusing on four main areas of research: the resolution of the vitamin D receptor crystal structure, the molecular details of 1,25-dihydroxyvitamin D3-mediated transcription, murine knockout models of key genes in the endocrine system, and alternative vitamin D receptors and ligands.