Edward Kuczynski

MARKERS OF RISK FOR PRETERM DELIVERY

Abstract Clinical and experimental evidence indicate that PTD results from four primary pathogenic mechanisms: activation of the maternal or fetal HPA axis; amniochorionic-decidual or systemic inflammation; decidual hemorrhage; and, pathologic distention of the myometrium. Each of these four pathways has a distinct epidemiological and clinical profile, and unique biochemical and biophysical pathways initiating parturition, but shares a common final biochemical pathway involving myometrial activation and stimulation, and enhanced genital tract protease activity promoting PPROM and cervical change. Traditional methods of predicting women at risk relying on obstetrical history or symptoms and epidemiological risk factors are neither sensitive nor specific. Recent approaches to predicting PTD, including sonographic measurement of cervical length and biochemical assays for hCG, cytokines, fFN, MMPs, estrogens, and CRH, are more sensitive than traditional methods. Moreover, given the heterogeneous, interactive etiopathogeneses of PTD, multiple biochemical markers should not only increase sensitivity and specificity, but also permit the detection of the relative contribution of each pathogenesis to the overall risk of PTD.

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.

Thrombin-enhanced matrix metalloproteinase-1 expression: a mechanism linking placental abruption with premature rupture of the membranes

Objective: Given the strong clinical association between the decidual hemorrhage of placental abruption and subsequent preterm premature rupture of the membranes, we assessed the effects of thrombin on the expression of the potent interstitial collagenase, matrix metalloproteinase-1 (MMP-1), in cultured endometrial stromal and decidual cells. Study design: Stromal cells derived from predecidualized cycling endometrium and decidual cells from term decidua were cultured in a defined medium containing estradiol, to mimic the hormonal milieu of the non-pregnant proliferative phase, or estradiol plus medroxyprogesterone acetate (MPA), to mimic the hormonal milieu of pregnancy, in the presence and absence of thrombin. Culture media were examined for MMP-1 protein levels and cell lysates were examined for steady-state MMP-1 mRNA levels. Results: MPA strongly inhibited MMP-1 levels in endometrial stromal and term decidual cells. However, thrombin overcame this suppression, producing MMP-1 levels that were several-fold higher than control levels. Conclusion: Extrapolation of thrombin-enhanced MMP-1 expression in cultured endometrial stromal and decidual cells to the in vivo pregnant state provides an explanation for the strong association between placental abruption and preterm membrane rupture.

Plasma levels of thrombin-antithrombin complexes predict preterm premature rupture of the fetal membranes

Objective: Decidual hemorrhage (abruption) is strongly associated with preterm premature rupture of fetal membranes (PPROM). Moreover, thrombin enhances decidual matrix metalloproteinase (MMP) expression, and MMP has been strongly linked to PPROM. The current study sought to determine whether increased thrombin activation, as assessed by circulating maternal plasma thrombin-antithrombin (TAT) complexes, predicted subsequent PPROM. Study design: We conducted a nested, case-control study of plasma TAT levels, measured by sensitive immunoassay, among 27 women with a singleton preterm birth preceded by PPROM and 54 matched, term controls. Receiver operating characteristic curve analysis was performed to identify the optimal TAT cut-off level predicting PPROM. Results: Mean gestational age at delivery in cases was 33.3 weeks, compared to 39.7 weeks in controls (p < 0.001). Compared with controls, women with PPROM had increased median plasma TAT levels in both the second trimester (5.1μg/l (range 2.2-26.3 μg/l) vs. 3.2 μg/l (range 1.3-7.3 μg/l); p = 0.001) and third trimester (7.0 μg/l (range 2.6-85.8 μg/dl) vs. 4.8 μg/l (range 1.7-15.4 μg/dl); p = 0.01). In the PPROM group, 16.0% of the women exhibited bleeding during the pregnancy, while the corresponding value among controls was 3.6% (p = 0.07). In the second trimester, the odds ratio for PPROM with a TAT level of > 3.9 μg/l was 6.0 (95% CI 1.67-21.1). This value predicted PPROM with a sensitivity of 88%, specificity of 68% and positive and negative predictive values of 82% and 97%, respectively. Conclusion: Second-trimester elevated plasma TAT concentrations are predictive of subsequent PPROM. These data provide further evidence that PPROM is associated with decidual thrombin activation.

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.

Preterm delivery and risk of subsequent cardiovascular morbidity and type‐II diabetes in the mother

Please cite this paper as: Lykke J, Paidas M, Damm P, Triche E, Kuczynski E, Langhoff‐Roos J. Preterm delivery and risk of subsequent cardiovascular morbidity and type‐II diabetes in the mother. BJOG 2010;117:274–281.

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

BackgroundOur investigation sought to compare changes in sexual function following supracervical hysterectomy (SCH) and total abdominal hysterectomy (TAH).MethodsA 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.ResultsForty-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).ConclusionsOur 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.

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.” LEVEL OF EVIDENCE: II-2

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 life‐saving drug in patients with massive PPH.

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% O2) 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.