An evolutionary genomic approach to identify genes involved in human birth timing.

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.

Investigation of genetic risk factors for chronic adult diseases for association with preterm birth.

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.

Impact of a comprehensive patient safety strategy on obstetric adverse events.

OBJECTIVE: We implemented a comprehensive strategy to track and reduce adverse events. STUDY DESIGN: We incrementally introduced multiple patient safety interventions from September 2004 through November 2006 at a university-based obstetrics service. This initiative included outside expert review, protocol standardization, the creation of a patient safety nurse position and patient safety committee, and training in team skills and fetal heart monitoring interpretation. We prospectively tracked 10 obstetrics-specific outcome. The Adverse Outcome Index, an expression of the number of deliveries with at least 1 of the 10 adverse outcomes per total deliveries, was analyzed for trend. RESULTS: Our interventions significantly reduced the Adverse Outcome Index (linear regression, r(2) = 0.50; P = .01) (overall mean, 2.50%). Concurrent with these improvements, we saw clinically significant improvements in safety climate as measured by validated safety attitude surveys. CONCLUSION: A systematic strategy to decrease obstetric adverse events can have a significant impact on patient safety.

Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia.

There is consensus that ischemia/reperfusion injury associated with preeclampsia (PE) promotes both placental damage and the release of factors leading to maternal endothelium dysfunction, a hallmark of this potentially life-threatening syndrome. These factors include plasminogen activator inhibitor-1 (PAI-1) and soluble fms-like tyrosine kinase-1 (sFlt-1). The goal of this study was to further characterize placental factors involved in the pathophysiology of PE. Thus, DNA microarray gene profiling was utilized to identify mRNA differentially regulated in placentas from women with severe PE compared to both preterm (PC) and term control (TC) groups. Microarray studies detected an upregulation of mRNA for ceruloplasmin, a copper-containing iron transport protein with antioxidant ferroxidase properties, in PE compared to PC and TC placentas, respectively. Quantitative real-time PCR confirmed these results by demonstrating significant increases in ceruloplasmin mRNA in PE vs PC and TC placentas. Supporting previous reports, the expression of sFlt-1 and PAI-1 were also upregulated in PE placentas. Immunohistochemistry localized ceruloplasmin to the intervillous space in PE and PC placentas, whereas stronger syncytial staining was noted in PE. Western blotting confirmed a significant increase in ceruloplasmin levels in placental tissue in PE compared to PC groups. PCR identified the presence of mRNA for ceruloplasmin in primary cultures of syncytiotrophoblasts, but not villous-derived fibroblasts, suggesting that syncytium is the site of ceruloplasmin synthesis in placenta. Hypoxic treatment (1% O(2)) of syncytiotrophoblasts enhanced levels of ceruloplasmin mRNA approximately 25-fold, a significantly greater upregulation than that noted for PAI-1 and sFlt-1, suggesting that enhanced ceruloplasmin expression is a sensitive marker of syncytial hypoxia. We suggest that syncytial ceruloplasmin and its associated ferroxidase activity, induced by the hypoxia accompanying severe PE, is important in an endogenous cellular program to mitigate the damaging effects of subsequent reperfusion injury at this site.

Fractional excretion of tumor necrosis factor-alpha in women with severe preeclampsia.

OBJECTIVE: Proinflammatory cytokines of placental or systemic origin are thought to play a central role in the pathophysiology of preeclampsia. We sought to estimate the fractional excretion of tumor necrosis factor (TNF)-alpha in relationship to proteinuria in women with severe preeclampsia. METHODS: In a cross-sectional study, we evaluated the serum and urine levels of TNF-alpha in 45 women diagnosed with severe preeclampsia (mean+/-standard error of the mean, gestational age 29.1+/-0.5 weeks). Forty-five healthy pregnant women matched for parity, maternal age, and gestational age at recruitment (30.1+/-0.4 weeks) made up the control group. Urinary concentrations were normalized to creatinine. The fractional excretion of TNF-alpha was interpreted in relationship to that of total proteins and soluble fms-like tyrosine kinase-1 (sFlt-1). RESULTS: We found that the women with preeclampsia had significantly higher serum TNF-alpha concentrations compared with the women in the control group (mean+/-standard error of the mean, preeclampsia: 1.39+/-0.09 versus control: 0.93+/-0.07 pg/mL, P<.001). In contrast, urinary levels of TNF-alpha were significantly decreased in the women with preeclampsia compared with the healthy women (median [interquartile range], preeclampsia: 0.26 [0.10-0.91] versus control: 0.58 [0.21-1.29] pg/mg creatinine, P=.003), even though the hypertensive women had higher levels of proteinuria. In contrast to sFlt-1, urinary TNF-alpha did not correlate with the degree of proteinuria. Additionally, in preeclampsia, the fractional excretion of TNF-alpha was significantly lower (preeclampsia: 1.92% [0.46-4.20] versus control: 7.2% [2.44-12.07], P<.001). CONCLUSION: The fractional excretion of TNF-alpha is significantly reduced in women with severe preeclampsia despite proteinuria. The decreased clearance and altered renal excretion of this cytokine may contribute to the exaggerated inflammatory response observed in preeclampsia. LEVEL OF EVIDENCE: II.

Chorionic villus sampling significantly affects fetal cardiovascular function.

OBJECTIVE: To assess the effects of chorionic villus sampling (CVS) on fetal heart rate (FHR). METHODS: A prospective longitudinal study was conducted among 300 patients undergoing transabdominal CVS between 8 and 13 weeks of gestation. Duration of the procedure, number of needle passes, sample weight, maternal age, fetal gender, and FHR response to CVS were recorded. RESULTS: The FHR before but not after CVS was inversely correlated with gestational age (r = -0.406, p < 0.001). Conversely, following CVS, no correlation was observed between FHR and gestational age (r = -0.06, p = 0.27). The difference between FHR after CVS and that obtained before CVS (delta FHR) increased with increasing gestational age at sampling (r = 0.372, p < 0.0001), decreased with increasing specimen weight (r = -0.16, p = 0.01) and increased with increasing maternal age (r = 0.22, p < 0.0001). Duration of the procedure, fetal gender and number of needle passes did not affect delta FHR. Multiple logistic regression indicated that gestational age at CVS and maternal age but not the other variables significantly affected delta FHR and together they accounted for over 22% of the variance (R(2) = 0.224, p < 0.0001). CONCLUSIONS: In summary, our results suggest that acute fetal hemodynamic changes accompany CVS and that these changes vary with gestational age.

Intercellular adhesion molecule-1 expression in human endometrium: implications for long term progestin only contraception.

BACKGROUND: Neutrophils infiltrate the endometrium pre-menstrually and after long-term progestin only-contraceptive (LTPOC) treatment. Trafficking of neutrophils involves endothelial cell-expressed intercellular adhesion molecule (ICAM-1). Previous studies observed that ICAM-1 was immunolocalized to the endothelium of endometrial specimens across the menstrual cycle, but disagreed as to whether extra-endothelial cell types express ICAM-1 and whether ICAM-1 expression varies across the menstrual cycle. METHODS: Endometrial biopsies were obtained from women across the menstrual cycle and from those on LTPOC treatment (either Mirena or Norplant). The biopsies were formalin-fixed and paraffin-embedded with subsequent immunohistochemical staining for ICAM-1. RESULTS: The current study found prominent ICAM-1 staining in the endometrial endothelium that was of equivalent intensity in different blood vessel types irrespective of the steroidal or inflammatory endometrial milieu across the menstrual cycle and during LTPOC therapy. Unlike the endothelial cells, the glands were negative and the stromal cells were weakly positive for ICAM immunostaining. CONCLUSION: The results of the current study suggest that altered expression of ICAM-1 by endothelial cells does not account for the influx of neutrophils into the premenstrual and LTPOC-derived endometrium. Such neutrophil infiltration may depend on altered expression of neutrophil chemoattractants.

Fractional excretion of angiogenic factors in women with severe preeclampsia.

OBJECTIVE: We estimated the fractional excretions of soluble fms-like tyrosine kinase 1 (sFlt-1), vascular endothelial growth factor, and placental growth factor of severely preeclamptic women at the time of disease clinical manifestation. METHODS: Levels of free sFlt-1, vascular endothelial growth factor, and placental growth factor were measured by immunoassay from time-matched serum-urine samples from 64 women in the following groups: nonpregnant reproductive aged (n = 9), healthy pregnant controls (n = 13), mildly preeclamptic women (n = 15), and women with severe preeclampsia (n = 27). Urinary concentrations of angiogenic factors were normalized to creatinine and fractional excretions calculated. Correlations were estimated between fractional excretions of angiogenic factors, albuminuria, nonspecific proteinuria and urine protein-to-creatinine ratio. RESULTS: Severely preeclamptic women had more than double urinary vascular endothelial growth factor (P = .01) and fractional excretion of vascular endothelial growth factor compared with mildly preeclamptic women (P = .007) or pregnant controls (P < .001). Serum, urine and fractional excretion levels of sFlt-1 were much higher among severely preeclamptic women compared with all the other pregnant groups (P < .001). Conversely, severely preeclamptic women had lower serum placental growth factor levels compared with healthy pregnant women (P < .05) and mildly preeclamptic groups (P < .05). Severely preeclamptic women had increased fractional excretions of placental growth factor, albumin, proteinuria, and random urine total protein/creatinine ratio. Among severely preeclamptic women there was no correlation between proteinuria and fractional excretion of vascular endothelial growth factor (r = 0.30, P = .127) or sFlt-1 (r = 0.35, P = .07). There was a significant correlation between fractional excretion for placental growth factor, random urine total protein/creatinine ratio (r = 0.60, P = .002), and nonspecific proteinuria (r = 0.50, P = .01). CONCLUSION: Severe preeclampsia is characterized by increased fractional excretion of angiogenic factors and especially of vascular endothelial growth factor, likely reflecting 2 separate phenomena that may have additive effects: "endogenous" renal production and glomerular "leakage."

Reduction of circulating annexin A5 levels and resistance to annexin A5 anticoagulant activity in women with recurrent spontaneous pregnancy losses.

OBJECTIVE: We investigated whether levels of annexin A5, evidence for resistance to annexin A5 activity, and levels anti-annexin A5 antibodies might be altered in women with a history of recurrent spontaneous pregnancy losses. STUDY DESIGN: These annexin A5 parameters were assayed in 70 nonpregnant women with a history of > or = 3 recurrent spontaneous pregnancy losses (cases) and 50 women without adverse pregnancy history (control subjects). RESULTS: Cases had significantly lower plasma annexin A5 levels than control subjects (median, 4.7 ng/mL [range, 0.3-40.4 ng/mL] vs 6.7 ng/mL [range, 0.7-56.0]; P = .01), significantly reduced anticoagulant ratios (188% [range, 119%-279%] vs 238% [range, 159%-286%]; P < .0001), and reduced binding of annexin A5 to phospholipid (6.3 ng/aliquot phospholipid [range, 1.5-16.4 ng/aliquot phospholipid] vs 9.7 ng/aliquot phospholipid (range, 3.5-17.0 ng/aliquot phospholipid]; P = .0002). There were no significant differences in anti-annexin A5 antibody levels. CONCLUSION: Reduction of annexin A5 and interference with its anticoagulant and binding activities are associated significantly with a history of recurrent spontaneous pregnancy losses. These data support the concept of a significant role for annexin A5 in the maintenance of pregnancy.

Analysis of circulating annexin A5 parameters during pregnancy: absence of differences between women with recurrent spontaneous pregnancy losses and controls.

OBJECTIVE: We investigated whether levels of annexin A5 (AnxA5), AnxA5 anticoagulant activity and binding, and anti-AnxA5 antibodies might be altered in women with previous histories of recurrent spontaneous pregnancy losses (RSPL) when tested during pregnancy. STUDY DESIGN: Ninety pregnant women with histories of 3 or more RSPL (cases) and 150 women without adverse pregnancy histories (controls) were assayed for these AnxA5 parameters. RESULTS: There were no significant differences between cases and controls in AnxA5 levels (median, 23.1 ng/mL [range, 2.1-201.1 ng/mL] vs 19.7 ng/mL [2.1-151.5 ng/mL]; P = .20), AnxA5 anticoagulant activity (183% [101%-236%] vs 168% [128%-256%]; P = .39) and binding (6.0 ng/aliquot PL [2.1-19.5 ng/aliquot PL) vs 6.1 ng/aliquot PL [1.6-16.8 ng/aliquot PL]; P = .72), and anti-AnxA5 antibody levels. CONCLUSIONS: AnxA5 parameters do not distinguish between cases and controls when tested during pregnancy. The pregnant state itself appears to be associated with altered levels of AnxA5 parameters.

Tibolone exerts progestational inhibition of matrix metalloproteinase expression in human endometrial stromal cells.

Tibolone and its metabolites were evaluated on matrix metalloproteinase (MMP) expression in human endometrial stromal cells (HESCs) under the hypothesis that these steroids would act as progestins on MMP-1, -2, and -3 expression. After 7 days of priming and 24h experimental incubation of confluent cultured HESCs, 10(-7) M medroxyprogesterone acetate (P) reduced MMP-1 to 49+/-34% (p<0.05) and MMP-3 to 33+/-22% of basal levels (mean+/-S.E.M., p<0.05, n=5). Although HESCs were unaffected by 10(-8) M estradiol (E), E+P reduced MMP-1 and MMP-3 levels an additional 2.5-fold from P alone. Tibolone and Delta-4 tibolone were equivalent to E+P in inhibiting MMP-1 and MMP-3 output, whereas 10(-6)M of 3alpha-OH or 3beta-OH tibolone was required to elicit significant inhibition of both MMPs (p<0.05). By contrast, none of the treatments affected HESC-secreted MMP-2 output. The ELISA results were confirmed by Western blotting and by substrate gel zymography. Quantitative RT-PCR demonstrated corresponding changes in MMP-1 and MMP-3 mRNA levels. Inhibition of MMP-1 and MMP-3 expression by tibolone and Delta-4 tibolone is consistent with the metabolism of tibolone to Delta-4 tibolone, and subsequent binding of Delta-4 tibolone to the progesterone receptor. Since 3alpha-OH and 3beta-OH tibolone bind exclusively to the estrogen receptor, their inhibition of MMP-1 and MMP-3 suggests metabolism by HESCs to Delta-4 tibolone. These observations help to explain the paradox that the endometrium becomes atrophic after tibolone administration despite the persistence in the circulation of 3alpha-OH and 3beta-OH tibolone, but not tibolone or Delta-4 tibolone.

Inflammatory cytokine and thrombin regulation of interleukin-8 and intercellular adhesion molecule-1 expression in first trimester human decidua.

CONTEXT: Decidual neutrophil infiltration complicates spontaneous abortions associated with inflammation and hemorrhage. Transendothelial neutrophil migration into inflamed tissues involves IL-8-mediated chemoattraction, then neutrophil attachment to endothelial cell-expressed intercellular adhesion molecule-1 (ICAM-1). OBJECTIVE: The aim of this study was to assess IL-8 and ICAM-1 regulation in decidual inflammation and hemorrhage; the effects of the proinflammatory cytokines, TNFalpha, IL-1beta and the hemostatic, proinflammatory cytokine thrombin were measured on IL-8 expression in first trimester decidual cells (DCs), and ICAM-1 immunostaining was compared in normal, inflamed, and hemorrhagic first trimester decidua. DESIGN: Immunohistochemistry of human decidua and in vitro treatment of human decidual cells were performed. SETTING: The study was conducted at the Academic Medical Center. INTERVENTION: . DCs were passaged until they were leukocyte-free (CD45 free by FACS), then were incubated with estradiol or medroxyprogesterone acetate alone or with TNFalpha or IL-1beta or thrombin. Normal, inflamed, and hemorrhagic decidua were immunostained for ICAM-1 and the neutrophil marker CD14. MAIN OUTCOME MEASURE: ICAM-1 immunostaining was performed in decidua. IL-8 levels in DC-conditioned media were assessed by ELISA and immunoblotting; IL-8 mRNA levels were measured by quantitative RT-PCR. RESULTS: Endothelial cell ICAM-1 immunostaining was similar in normal and inflamed or hemorrhagic decidua. In cultured DCs, optimal concentrations of IL-1beta, TNFalpha, and thrombin elevated secreted IL-8 levels by 1083 +/- 261-, 370 +/- 77-, and 45 +/- 15-fold, respectively (mean +/- SEM; P < 0.05; n = 8). The effects were dose dependent and were unaffected by medroxyprogesterone acetate. Western blotting confirmed the ELISA results, and corresponding effects on IL-8 mRNA levels were observed. CONCLUSIONS: Cytokine/thrombin-enhanced DC IL-8 expression interacts with constitutively expressed ICAM-1 in decidual endothelium to modulate neutrophil trafficking into hemorrhagic and inflamed first trimester decidua.

Tibolone and its metabolites enhance tissue factor and PAI-1 expression in human endometrial stromal cells: Evidence of progestogenic effects.

Tibolone is a highly effective postmenopausal hormone treatment that has its biological activity dependent on metabolism to 3alpha- and 3beta-OH tibolone, which bind solely to the estrogen receptor. Despite the high levels of estrogen receptor-binding metabolites in the circulation, the endometrium becomes atrophic, suggesting inactivation of the estrogen response in this tissue which may be due to the progestogenic activity of tibolone and the Delta-4 tibolone metabolite. We evaluated the effects of tibolone and its metabolites on tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI-1) expression in human endometrial stromal cells (HESCs). Since TF and PAI-1 exhibit long-term in vivo and in vitro up-regulation by progestin they serve as endpoints for assessing chronic effects of progestin exposure. Confluent HESCs were primed in serum-containing medium with vehicle control, 10(-8)mol/L estradiol, 10(-7)mol/L medroxyprogesterone acetate, or 10(-8) to 10(-6)mol/L tibolone or its metabolites, then switched to a defined medium with corresponding vehicle or steroids. After 24h, ELISAs indicated that the progestin elevated TF (6.2-fold +/-3.0; p<0.05) and PAI-1 (eight-fold +/-2.1; p<0.05) levels, whereas the cells were refractory to estradiol exposure. Tibolone and Delta-4 tibolone (10(-8) to 10(-6)mol/L) were as effective as 10(-7)mol/L medroxyprogesterone acetate in enhancing TF and PAI-1 output (p<0.05). Unexpectedly, at the higher concentrations 3alpha- and 3beta-OH tibolone also elevated TF and PAI-1 expression (p<0.05). Western blotting confirmed the ELISA results. Our findings suggest that HESCs metabolize 3alpha- and 3beta-OH tibolone to tibolone and subsequently to Delta-4 tibolone, which can both stimulate the progesterone receptor. Since TF and PAI-1 promote hemostasis by complementary mechanisms, our findings account for the reduced occurrence of abnormal uterine bleeding associated with tibolone therapy.

Maternal thrombophilias are not associated with early pregnancy loss.

We investigated the association between inherited and acquired maternal thrombophilias and adverse pregnancy events. A cohort of 491 patients with a history of adverse pregnancy outcomes was evaluated for activated protein C resistance, factor V Leiden and prothrombin G20210A mutations, hyperhomocysteinemia, deficiencies of antithrombin, protein C and S and both anticardiolipin antibodies and lupus anticoagulants. The study had an 80% power to detect a 15% difference in the prevalence of thrombophilia for 1(st) trimester loss. In our high-risk cohort the presence of 1 maternal thrombophilia or more than one thrombophilia were found to be protective of recurrent losses at < 10 weeks (1 thrombophilia: OR: 0.55, 95% CI: 0.33-0.92; > 1 thrombophilia: OR: 0.48, 95%CI:0.29-0.78). In contrast, the presence of maternal thrombophilia(s) was modestly associated with an increased risk of losses > 10 weeks (1 thrombophilia: OR:1.76, 95%CI: 1.05-2.94, >1 thrombophilia: OR:1.66, 95%CI:1.03-2.68). Women who experienced only euploid losses were not more likely to have an identified thrombophilia than women who experienced only aneuploid losses (OR 1.03; 0.38-2.75). The presence of maternal thrombophilia was associated with an increased risk of fetal loss after 14 weeks, fetal growth restriction, abruption and preeclampsia. There was a significant "dose-dependent" increase in the risk of abruption (OR:3.60, 95%CI: 1.43-9.09) and preeclampsia (OR:3.21, 95%CI:1.20-8.58). In conclusion, these data indicate maternal thrombophilias are not associated with pregnancy wastage prior to 10 weeks of gestation.

Increased rates of chorioamnionitis with extra-amniotic saline infusion method of labor induction.

OBJECTIVE: Extra-amniotic saline infusion has been shown to be equal to or more efficacious than misoprostol, laminaria, dinoprostone, and prostaglandin estradiol for cervical ripening and labor induction. Because of the introduction of a foreign body into the uterus, extra-amniotic saline infusion may potentially cause increased rates of chorioamnionitis. This study examines the risk of chorioamnionitis with extra-amniotic saline infusion compared with other methods of induction and spontaneous labor. METHODS: A retrospective analysis was performed based on deliveries at Bellevue Hospital Center, a tertiary-care facility, from August 2000 to December 2002. Three groups were identified: extra-amniotic saline infusion, other methods of induction, and spontaneous labor. Differences in chorioamnionitis rates were analyzed by using analysis of variance and multivariable logistic regression as appropriate. RESULTS: There were 625 charts evaluated: 171 extra-amniotic saline infusion, 190 other, and 264 with spontaneous labor. The rates of chorioamnionitis were 26.9%, 17.9%, and 13.3%, respectively. After adjusting for confounding variables, such as instrumentation, length of rupture, and number of exams, subjects who were induced with extra-amniotic saline infusion were significantly more likely to develop chorioamnionitis (relative risk = 2.2; 95% confidence interval 1.4, 4.0; P =.006). CONCLUSION: Extra-amniotic saline infusion may be associated with a greater risk of chorioamnionitis when compared with other methods of labor induction. Given the increased risk of chorioamnionitis associated with extra-amniotic saline infusion, its use should be in the context of a careful assessment of the risks and benefits of various methods of labor induction. LEVEL OF EVIDENCE: II-2

Supracervical hysterectomy versus total abdominal hysterectomy: perceived effects on sexual function.

BACKGROUND: Our investigation sought to compare changes in sexual function following supracervical hysterectomy (SCH) and total abdominal hysterectomy (TAH). METHODS: A retrospective chart review was performed to identify all patients who underwent supracervical hysterectomy or total abdominal hysterectomy at a tertiary care center. Patients who met criteria for participation were sent a one page confidential, anonymous questionnaire to assess sexual function experienced both pre- and postoperatively. A total of 69 patients in each group were eligible for participation. A multiple logistic regression model was used to analyze measured variables. RESULTS: Forty-eight percent (n = 33) of women undergoing a SCH returned the questionnaire, while 39% (n = 27) of those undergoing a TAH chose to participate. There were no significant demographic differences between the two groups. Patients who underwent TAH reported worse postoperative sexual outcome than SCH patients with respect to intercourse frequency, orgasm frequency and overall sexual satisfaction (P = 0.01, 0.03, and 0.03, respectively). Irrespective of type of hysterectomy, 35% of patients who underwent bilateral salpingoophorectomy (BSO) with hysterectomy experienced worse overall sexual satisfaction compared to 3% of patients who underwent hysterectomy alone (P = 0.02). CONCLUSIONS: Our data suggest that TAH patients experienced worse postoperative sexual function than SCH patients with respect to intercourse frequency and overall sexual satisfaction. Irrespective of type of hysterectomy, patients who underwent bilateral salpingoophorectomy experienced worse overall sexual satisfaction.

Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth.

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.

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 chi(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/m(2) (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.

Use of recombinant activated factor VII for massive postpartum hemorrhage.

OBJECTIVE: We hypothesised that patients with massive postpartum hemorrhage (PPH), defined as blood loss >1,500 ml,may benefit from the use of activated recombinant factor VII (rFVIIa). Design. Retrospective cohort study. Setting.Department of Obstetrics & Gynaecology, Dow University of Health Sciences. POPULATION: Thirty-four women with a diagnosis of massive PPH. METHODS: All patients with PPH who were admitted to the Department of Obstetrics &Gynecology and Surgical Intensive Care Unit of Civil Hospital Karachi, Pakistan, were included in the study. From March 2005 to October 2006, 34 patients fulfilled the criteria of massive PPH, of which 18 received rFVIIa to control bleeding, and 16 patients did not. Availability and cost of rFVIIa were the factors in drug allocation. Main outcome measures. Maternal mortality, correction of coagulopathy, the amount of blood products transfused and preservation of fertility. RESULTS: Patients receiving rFVIIa had lower maternal mortality (5/18, 28% versus 8/16, 50%, OR: 0.04 (0.002, 0.83)), and received a lower number of packed red cell transfusions (4.0 ± 4.46 versus 9.61 ± 6.7, p value 0.007), against the comparison group. Patients receiving rFVIIa had lower activated partial thromboplastin (median: 13.0; 25-75th percentile: -25.0, -8.0, signed rank p<0.0001), and lower prothrombin times (median: -8.8; 25-75th percentile: -24.2, -4.8), after administration of drug.There was no significant difference in the rate of hysterectomy between the 2 groups (11/18 (61%) versus 6/16 (38%)). No adverse event attributable to rFVIIa was observed in the study. CONCLUSION: Activated recombinant factor VII can be a lifesaving drug in patients with massive PPH.