Mourad Dahhou

Stress Pathways to Spontaneous Preterm Birth: The Role of Stressors, Psychological Distress, and Stress Hormones

The authors investigated a large number of stressors and measures of psychological distress in a multicenter, prospective cohort study of spontaneous preterm birth among 5,337 Montreal (Canada)-area women who delivered from October 1999 to April 2004. In addition, a nested case-control analysis (207 cases, 444 controls) was used to explore potential biologic pathways by analyzing maternal plasma corticotrophin-releasing hormone (CRH), placental histopathology, and (in a subset) maternal hair cortisol. Among the large number of stress and distress measures studied, only pregnancy-related anxiety was consistently and independently associated with spontaneous preterm birth (for values above the median, adjusted odds ratio = 1.8 (95% confidence interval: 1.3, 2.4)), with a dose-response relation across quartiles. The maternal plasma CRH concentration was significantly higher in cases than in controls in crude analyses but not after adjustment (for concentrations above the median, adjusted odds ratio = 1.1 (95% confidence interval: 0.8, 1.6)). In the subgroup (n = 117) of participants with a sufficient maternal hair sample, hair cortisol was positively associated with gestational age. Neither maternal plasma CRH, hair cortisol, nor placental histopathologic features of infection/inflammation, infarction, or maternal vasculopathy were significantly associated with pregnancy-related anxiety or any other stress or distress measure. The biologic pathways underlying stress-induced preterm birth remain poorly understood.

Mortality Risk Among Children Initially Treated With Dialysis for End-Stage Kidney Disease, 1990–2010

IMPORTANCE Most children with end-stage kidney disease (ESKD) are treated with dialysis prior to transplant. It is not known whether their outcomes have changed in recent years. OBJECTIVE To determine if all-cause, cardiovascular, and infection-related mortality rates for children and adolescents beginning dialysis improved between 1990 and 2010. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of patients younger than 21 years initially treated with dialysis for ESKD, recorded in the United States Renal Data System between 1990 and 2010. Children with a prior kidney transplant were excluded. We used Cox proportional hazard models to estimate the hazard ratios (HRs) for mortality associated with a 5-year increment in year of ESKD treatment initiation. Primary analyses censored observation at kidney transplant. MAIN OUTCOMES AND MEASURES All-cause, cardiovascular, and infection-related mortality. RESULTS A total of 3450 children younger than 5 years and 19,951 children 5 years or older started dialysis from 1990-2010. Of those younger than 5 years, 705 died during dialysis treatment (98.8/1000 person-years); mortality rates were 112.2 and 83.4 per 1000 person-years in those initiating dialysis in 1990-1994 and 2005-2010, respectively. Of those 5 years and older at treatment initiation, 2270 died during dialysis treatment (38.6/1000 person-years). Their mortality rates were 44.6 and 25.9 per 1000 person-years in those initiating dialysis in 1990-1994 and 2005-2010, respectively. Each 5-year increment in calendar year of dialysis initiation was associated with an adjusted HR of 0.80 (95% CI, 0.75-0.85) among children younger than 5 years at initiation and an HR of 0.88 (95% CI, 0.85-0.92) among those 5 years and older. RESULTS A total of 23,401 children and adolescents who initiated ESKD treatment with dialysis at younger than 21 years between 1990 and 2010 were identified. Crude mortality rates during dialysis treatment were higher among children younger than 5 years at the start of dialysis compared with those who were 5 years and older. Mortality rates for both children and adolescents being treated for ESKD with dialysis decreased significantly between 1990 and 2010. CONCLUSIONS AND RELEVANCE In the United States, there was a substantial decrease in mortality rates over time among children and adolescents initiating ESKD treatment with dialysis between 1990 and 2010. Further research is needed to determine the specific factors responsible for this decrease.

Risk Factors for Postpartum Hemorrhage: Can We Explain the Recent Temporal Increase?

OBJECTIVE To assess risk factors for postpartum hemorrhage (PPH) and the extent to which changes in those risk factors may explain the rising incidence of PPH recently reported from industrialized countries. METHODS We carried out a hospital-based cohort study of 103 726 consecutive deliveries from January 1, 1978, to January 31, 2007, from the computerized medical records of a tertiary-care university maternity hospital in Montreal. We examined adjusted odds ratios for any PPH (estimated blood loss > 500 mL for vaginal deliveries, > 1000 mL for Caesarean sections), severe PPH (estimated blood loss ≥ 1500 mL), and PPH accompanied by blood transfusion and/or hysterectomy. RESULTS Major independent risk factors for PPH included primiparity, prior Caesarean section, placenta previa or low-lying placenta, marginal umbilical cord insertion in the placenta, transverse lie, labour induction and augmentation, uterine or cervical trauma at delivery, gestational age < 32 weeks, and birth weight ≥ 4500 g. An overall increase in rate of PPH over the study period (OR 1.029; 95% CI 1.024 to 1.034 per year) disappeared (OR 0.995; 95% CI 0.988 to 1.001 per year) after inclusion of maternal age, parity, prior Caesarean section, labour induction and augmentation, placenta previa or low-lying placenta, and abnormal placenta, with most of the reduction attributable to rises in previous Caesarean section and labour augmentation. CONCLUSION Labour induction, augmentation of labour, and prior Caesarean section are significantly associated with the risk of PPH, and their increase over the study period largely explains the observed rise in PPH.

Association between age and graft failure rates in young kidney transplant recipients.

Background. Age at transplant and graft failure risk are associated in young kidney transplant recipients. The risk of graft failure may also vary by current age, irrespective of age at transplant. We sought to estimate age-specific graft failure rates in young kidney transplant recipients and to estimate the relative hazards of graft failure at different ages, compared with at the age of 25 to 29 years. Methods. We evaluated 90,689 patients recorded in the United States Renal Data System database who received a first transplant when younger than 40 years (1988–2009); 18,310 were younger than 21 years at transplant. Time-dependent Cox models with time-varying covariates were used to estimate the association between age (time-dependent) and death-censored graft failure risk, adjusted for time since transplant and other potential confounders. Results. There were 31,857 graft failures over a median follow-up of 5.9 years (interquartile range, 2.5–10.5 years; maximum, 21.8 years). Crude age-specific graft failure rates were highest in 19 year olds (6.6 per 100 person-years). Compared with individuals with the same time since transplant observed at 25 to 29 years of age, death-censored graft failure rates were highest in 17 to 24 year olds (hazard ratio, 1.20; [95% confidence interval 1.13, 1.27] for 17–20 year olds and 1.20 [1.13, 1.26] for 21–24 year olds; both P<0.0001) and lowest in 5 to 12 year olds (hazard ratio, 0.60; [0.53, 0.68] for 5–9 year olds and 0.56 [0.49, 0.64] for 10–12 year olds; both P<0.0001). Conclusion. Among first kidney transplant recipients younger than 40 years, older adolescents and young adults (17–24 years) have the highest risk of graft failure, irrespective of age at transplant.

Vasculopathic and thrombophilic risk factors for spontaneous preterm birth

BACKGROUND Mothers who give birth to preterm infants are at increased risk of mortality from coronary heart disease and stroke, but the biological pathways underlying these associations have not been explored. METHODS We carried out a case-control study nested in a large (n = 5337) prospective, multicentre cohort. All cohort women had an interview, examination and venipuncture at 24-26 weeks. Frozen plasma samples in spontaneous preterm births (n = 207) and 444 term controls were analysed for plasma homocysteine, folate, cholesterol (total, low-density lipoprotein and high-density lipoprotein) and thrombin-antithrombin (TAT) complexes. DNA was extracted and analysed for seven gene polymorphisms involved in thrombophilia or folate or homocysteine metabolism. Fresh placentas were fixed, stained and blindly assessed for histologic evidence of infarction and decidual vasculopathy. RESULTS High (above the median) plasma homocysteine and HDL cholesterol were significantly and independently associated with the risk of spontaneous preterm birth [adjusted odds ratios (OR)s = 1.9 (95% 1.1-3.3) and 0.5 (0.3-0.9), respectively]. A higher proportion of women with high homocysteine concentrations had decidual vasculopathy [(13.0 vs 6.8%; OR = 1.9 (1.1-3.5)], although the positive association between decidual vasculopathy and preterm birth did not achieve statistical significance [OR = 1.5 (0.9-2.7)]. No significant associations were observed with the DNA polymorphisms or with plasma TAT or folate levels. CONCLUSIONS Similar vasculopathic risk factors may underlie preterm birth and adult coronary heart disease and stroke.

The low prevalence of allergic disease in Eastern Europe

Background The prevalence of allergic disease is known to be low in Eastern Europe.

Mid-trimester maternal plasma cytokines and CRP as predictors of spontaneous preterm birth.

Most previous studies of maternal cytokines and preterm birth have analyzed immunologic biomarkers after the onset of labor or membrane rupture; fewer have examined the systemic (blood) immune response prior to labor onset. We carried out a case-control study nested in a large (n=5337) prospective, multi-center cohort. Cohort women had an interview, examination, and venipuncture at 24-26 weeks. Frozen plasma samples in women with spontaneous preterm birth (n=207) and approximately 2 term controls per case (n=444) were analyzed using Luminex multianalyte profiling technology. Fresh placentas were fixed, stained, and blindly assessed for histologic evidence of infection/inflammation, decidual vasculopathy, and infarction, and vaginal swabs were analyzed for bacterial vaginosis and fetal fibronectin concentration. High maternal matrix metalloproteinase-9 (MMP-9) concentration, but none of the other cytokines or C-reactive protein (CRP), was significantly associated with spontaneous preterm birth [adjusted OR=1.7 (1.1-2.4)] and showed a dose-response relation across quartiles. No association was observed, however, between maternal MMP-9 and placental infection/inflammation, bacterial vaginosis, or vaginal fetal fibronectin concentration. Our results require confirmation in future studies but suggest that a systemic immune response implicating MMP-9 may have an etiologic role in spontaneous preterm birth.

The double jeopardy of clustered measurement and cluster randomisation

Michael S Kramer and colleagues suggest that double clustering might explain the negative results of some cluster randomised trials and describe some strategies for avoiding the problem

Relative importance of HLA mismatch and donor age to graft survival in young kidney transplant recipients.

Background The American deceased-donor (DD) kidney allocation algorithm for children emphasizes the importance of younger donors and shorter waiting times over human leukocyte antigen (HLA) matching. We sought to compare the relative importance of donor age with that of HLA mismatching (MM) on graft survival. Methods We studied patients less than 21 years old recorded in the U.S. Renal Data System, who received a first transplant from a DD 5 years old or younger or from a living donor (LD). Using separate Cox proportional hazards models for DD and LD recipients, we estimated the adjusted 5-year probability of graft survival for each donor age–HLA MM combination and compared estimated graft survival across the different HLA MM–donor age combinations. Results Both donor age and HLA MM were significantly associated with DD graft survival, whereas only HLA MM had a significant association with LD graft survival. Compared with DD grafts from less than 35-year-old 4–6 MM donors, survival was not significantly different for 0–1 and 2–3 MM grafts from 35- to 44-year-old donors or for 0–1 MM grafts from donors 45 years old or older. The most poorly matched grafts from the oldest LD had survival similar to or better than any DD. Conclusions Donor age and HLA MM both play important roles in determining DD graft survival. The advantages of younger donors offset the disadvantages of poorer HLA matching, and better HLA matching offsets the disadvantages of older donor age.

Maternal Stress/Distress, Hormonal Pathways and Spontaneous Preterm Birth

BACKGROUND Although second-trimester blood corticotrophin-releasing hormone (CRH) levels are robustly associated with preterm birth, the findings with respect to cortisol have been inconsistent, as have been those relating stress hormones to measured stressors and maternal distress. METHODS We measured plasma CRH, adrenocorticotrophic hormone (ACTH), cortisol, cortisol-binding globulin, oestradiol and progesterone at 24-26 weeks in a nested case-control study of 206 women who experienced spontaneous preterm birth and 442 term controls. We also related the hormonal levels to measures of environmental stressors, perceived stress and maternal distress (also assessed at 24-26 weeks) and to placental histopathology. RESULTS With the exception of an unexpectedly low oestradiol:progesterone ratio among cases (adjusted odds ratio = 0.5 [95% confidence interval 0.3, 0.8] for ratios above the median in controls), none of the hormonal measures was independently associated with spontaneous preterm birth; placental histopathological evidence of infection/inflammation, infarction or decidual vasculopathy; or measures of maternal stress or distress. CRH levels were positively associated with cortisol, but not with ACTH, whereas ACTH was also positively associated with cortisol. CONCLUSIONS Our findings suggest an intact pituitary-adrenal axis and confirm the positive feedback effect of cortisol on (placental) CRH. Neither of these hormonal pathways, however, was strongly linked to maternal stress/distress or to the risk of spontaneous preterm birth.