Morgan R. Peltier

Recurrence of Ischemic Placental Disease

OBJECTIVE: To test the hypothesis that the presence of preeclampsia, small for gestational age (SGA)-birth, and placental abruption in the first pregnancy confers increased risk in the second pregnancy. METHODS: A retrospective cohort study entailing a case–crossover analysis was performed based on women who had two consecutive singleton live births (n=154,810) between 1989 and 1997 in Missouri. Small for gestational age was defined as infants with birth weight below the 10th centile for gestational age. Risk and recurrence of ischemic placental disease was assessed from fitting logistic regression models after adjusting for several confounders. RESULTS: Preeclampsia in the first pregnancy was associated with significantly increased risk of preeclampsia (odds ratio 7.03, 95% confidence interval 6.51, 7.59), SGA (odds ratio 1.16, 95% confidence interval 1.06, 1.27), and placental abruption (odds ratio 1.90, 95% confidence interval 1.51, 2.38) in the second pregnancy. Similarly, women with SGA and abruption in the first pregnancy were associated with increased risks of all other conditions in the second pregnancy. CONCLUSION: Women with preeclampsia, SGA, and placental abruption in their first pregnancy—conditions that constitute ischemic placental disease—are at substantially increased risk of recurrence of any or all these conditions in their second pregnancy. Although causes of these conditions remain largely speculative, these entities may manifest through a common pathway of ischemic placental disease with significant risk of recurrence. LEVEL OF EVIDENCE: II

Placental Abruption in Term and Preterm Gestations: Evidence for Heterogeneity in Clinical Pathways

OBJECTIVE: To estimate the magnitude of associations of acute and chronic processes with abruption in preterm and term gestations. METHODS: A retrospective cohort study was performed using data on women that delivered singleton live births and stillbirths at 20 or more weeks of gestation in the United States, 1995–2002 (n = 30,378,902). Rates of 1) acute-inflammation–associated clinical conditions (premature rupture of membranes and intrauterine infection); 2) chronic processes associated with vascular dysfunction or chronic inflammation (chronic and pregnancy-induced hypertension, preexisting or gestational diabetes, small for gestational age, and maternal smoking); and 3) both acute and chronic processes, were examined among women with and without abruption. Rates were examined separately among preterm (< 37 weeks) and term births, with adjustment for confounders. Relative risk (RR) for aforementioned groups in relation to abruption was derived from multivariate logistic regression models after adjusting for potential confounders. RESULTS: At preterm gestation, the rates of acute-inflammation–associated conditions were higher among women with than without abruption (12.0% compared with 10.2%; RR 1.38, 95% confidence interval [CI] 1.34–1.42). At term, acute-inflammation–associated conditions were present in 4.2% and 3.3% of births with and without abruption, respectively (RR 1.39, 95% CI 1.33–1.45). At preterm gestation, the rates of chronic processes were 43.9% and 30.0% among women with and without abruption, respectively (RR 1.87, 95% CI 1.85–1.90). At term, the corresponding rates of chronic processes were 41.0% and 22.7%, respectively (RR 2.37, 95% CI 2.34–2.41). Association between both acute and chronic processes and abruption are similar to those of acute-inflammation–associated conditions. CONCLUSION: Among women with placental abruption, conditions associated with acute inflammation are more prevalent at preterm than term gestations, whereas chronic processes are present throughout gestation. LEVEL OF EVIDENCE: II-2

Acute and chronic respiratory diseases in pregnancy: Associations with spontaneous premature rupture of membranes

Objective. To examine whether acute and chronic respiratory diseases are associated with an increased risk of spontaneous premature rupture of the membranes (PROM). Methods. We used the 1993–2004 National Hospital Discharge Survey data of singleton deliveries in the USA (N = 41 250 539). The International Classification of Diseases Ninth Revision was utilized to identify acute (acute upper respiratory diseases, viral/bacterial pneumonia, and acute bronchitis/bronchiolitis) and chronic (chronic bronchitis and asthma) respiratory conditions and spontaneous PROM. All analyses were adjusted for potential confounders. Results. The incidence of PROM was 5%, and rates of acute and chronic respiratory conditions were 2.1 and 9.5 per 1000 pregnancies, respectively. Chronic bronchitis was associated with a reduced risk of PROM (RR 0.39, 95% CI 0.31, 0.48). Asthma was significantly associated with PROM at preterm (RR 1.15, 95% CI 1.14, 1.17) and term (RR 1.27, 95% CI 1.23, 1.30). Stratification by race showed that acute upper respiratory disease was associated with preterm PROM in whites (RR 1.90, 95% CI 1.71, 2.11) and blacks (RR 6.76, 95% CI 5.67, 8.07). Viral/bacterial pneumonia was associated with preterm PROM in blacks and term PROM in both races. Asthma was associated with term PROM in blacks but not whites. Conclusions. Acute respiratory diseases and asthma during pregnancy are associated with spontaneous PROM, with substantially stronger association among blacks than whites. We speculate that timely diagnosis and treatment, coupled with closely mentoring of pregnant women may help reduce the rate of PROM and associated complications.

Characterization of the Macrophage-Stimulating Activity from Ureaplasma urealyticum

Intra‐amniotic infection is the most common cause of preterm labor. Infections are thought to cause preterm labor by increasing the production of proinflammatory cytokines at the maternal–fetal interface. Experiments with cell culture and animal models have indicated that bacterial lipopolysaccharide (LPS) increases the production of proinflammatory cytokines in reproductive tissues. The majority of intrauterine infections, however, are associated with Ureaplasma urealyticum, which does not contain LPS. Therefore, we performed a series of experiments to understand better the bacterial factor(s) that are responsible for the proinflammatory effects of U. urealyticum.

ORIGINAL ARTICLE: Effect of Progesterone on Proinflammatory Cytokine Production by Monocytes Stimulated with Pathogens Associated with Preterm birth

Problem A number of clinical trials have demonstrated that supplemental progesterone (P4) can prevent preterm birth. Although P4 can decrease the production of mediators of inflammation by lipopolysaccharide (LPS)‐stimulated macrophages, a majority of infections associated with preterm birth are due to Ureaplasma urealyticum, which does not contain LPS. Therefore, we studied whether P4 could lower the production of proinflammatory cytokines by monocytes stimulated with U. urealyticum.

Primiparity: An 'intermediate' risk group for spontaneous and medically indicated preterm birth

Objective.u2003Most women in their first pregnancy are at ‘unknown’ risk for preterm birth. We hypothesized that such women may be at an increased risk for preterm birth in comparison to those with a prior term birth. Methods.u2003We used Missouris maternally-linked data (1989–97), comprised of women delivering their first singleton live birth (N = 259 431) and women delivering their first two consecutive singleton live births (N = 154 810). We compared preterm birth (<37 weeks) rates among women with a previous term birth, women with no reproductive history (primiparous women), and in those with a previous preterm birth. Risks of spontaneous and medically indicated preterm birth were also examined after adjustments for confounders through multivariate log-binomial regression models. Results.u2003Preterm birth rates were 8.1%, 9.6%, and 23.3% among women with a previous term birth, among primiparous women, and among those with a previous preterm birth, respectively. In comparison to women with a prior term birth, risks of spontaneous preterm birth among primiparous women and among women with a prior preterm birth were 1.1-fold (95% confidence interval (CI) 1.0, 1.2) and 2.5-fold (95% CI 2.4, 2.6) higher, respectively. These risks were higher for medically indicated preterm birth among both primiparous women (RR 1.3, 95% CI 1.2, 1.4) and those with a prior preterm birth (RR 3.2, 95% CI 3.0, 3.5) than for spontaneous preterm births. Conclusions.u2003Primiparous women are at increased risk of both medically indicated and spontaneous preterm birth. The findings suggest that studies on preterm birth should consider a risk assignment to include three groups: low-risk (prior term birth), intermediate risk (primiparity), and high-risk (prior preterm birth). This strategy will be informative for the identification of women with impending risk of delivering preterm, and complications associated with prematurity.

Isolation and Partial Purification of Macrophage- and Dendritic Cell-Activating Components from Mycoplasma arthritidis: Association with Organism Virulence and Involvement with Toll-Like Receptor 2

ABSTRACT Mycoplasma arthritidis induces toxicity, arthritis, and dermal necrosis in mice. Virulence factors include a superantigen and membrane adhesins and possibly also a bacteriophage component. Here we compare the biological properties of Triton X-114 extracts derived from avirulent and virulent M. arthritidis strains. Macrophage cell lines and resident peritoneal macrophages were used to assess inflammatory potential as indicated by production of tumor necrosis factor alpha, interleukin-6, and/or nitric oxide. The activity resided exclusively within the hydrophobic detergent phase, was unaffected by heat treatment at 100°C for 30 min, and was resistant to proteinase K digestion, suggesting involvement of a lipopeptide. Contamination of extracts with endotoxin or superantigen was excluded. Extracts of the more virulent strain had higher activity than did those of the avirulent strain. Using CHO cells expressing Toll-like receptor 2 (TLR2) or TLR4, both with transfected CD14, we showed that extracts activated these cells via TLR2 but not by TLR4. Also, macrophages from C57BL/6 TLR2−/− mice failed to respond to the extracts, whereas those from TLR2+/+ cells did respond. The preparations from the virulent strain of M. arthritidis were also more potent in activating dendritic cells, as evidenced by up-regulation of major histocompatibility complex class II, CD40, B7-1, and B7-2. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and subsequent elution of gel slices revealed the presence of three active moieties which corresponded to molecular masses of approximately 24, 28, and 40 kDa. Three active components were also found by reverse-phase chromatography. We suggest that macrophage activation by M. arthritidis could play a significant role in the inflammatory response induced in the host by this organism.

Reduced folate carrier 80A→G polymorphism, plasma folate, and risk of placental abruption

Folate deficiency and maternal smoking are strong risk factors for placental abruption. We assessed whether the reduced folate carrier [NM_194255.1: c.80A→G (i.e., p.His27Arg)] (RFC-1) polymorphism was associated with placental abruption, and evaluated if maternal smoking modified the association between plasma folate and abruption. Data were derived from the New Jersey-Placental Abruption Study—a multicenter, case-control study of placental abruption (2002–2007). Maternal DNA was assayed for the RFC-1 c.80A→G polymorphism using a PCR-dependent diagnostic test. Maternal folate (nmol/l) was assessed from maternal plasma, collected immediately following delivery. Due to assay limitations, folate levels at ≥60xa0nmol/l were truncated at 60xa0nmol/l. Therefore, case–control differences in folate were assessed from censored log-normal regression models following adjustment for potential confounders. Distribution of the mutant allele (G) of the RFC-1 c.80A→G polymorphism was similar between cases (52.3%; nxa0=xa0196) and controls (50.5%; nxa0=xa0191), as was the homozygous mutant (G/G) genotype (OR 1.1, 95% CI 0.6–2.2). In a sub-sample of 136 cases and 140 controls, maternal plasma folate levels (meanxa0±xa0standard error) corrected for assay detection limits were similar between placental abruption cases (63.6xa0±xa05.1xa0nmol/l) and controls (58.3xa0±xa04.7xa0nmol/l; Pxa0=xa00.270), and maternal smoking did not modify this relationship (interaction Pxa0=xa00.169). We did not detect any association between the RFC-1 c.80A→G polymorphism and placental abruption, nor was an association between plasma folate and abruption risk evident. These findings may be the consequence of high prevalence of prenatal multivitamin and folate supplementation in this population (over 80%). It is therefore not surprising that folate deficiency may be rare and that the RFC-1 c.80A→G polymorphism is less biologically significant for placental abruption.

ORIGINAL ARTICLE: Can Sulfasalazine Prevent Infection-Mediated Pre-Term Birth in a Murine Model?

Citation Nath CA, Ananth CV, Smulian JC, Peltier MR. Can sulfasalazine prevent infection‐mediated pre‐term birth in a murine model? Am J Reprod Immunol 2010; 63: 144–149

Is the Risk of Autism in Younger Siblings of Affected Children Moderated by Sex, Race/Ethnicity, or Gestational Age?

Objective: To evaluate the recurrence risk of autism spectrum disorders (ASD) in younger siblings of affected children and determine how it is modified by race/ethnicity and sex. Method: Medical records of children born in a large health maintenance organization (Kaiser Permanent Southern California) hospitals from January 1, 2001, through December 31, 2010, and who remained in our system until 2 to 11 years of age were used to assess the risk of recurrence of ASD in younger siblings. Children born at <28 or >42 weeks gestation, multiple births, or those who were not active members for ≥3 months were excluded. ASD diagnosis was ascertained from DSM-IV codes, and the magnitude of the association was estimated using adjusted relative risks (aRRs). Results: Among eligible younger siblings, 592 (1.11%) had the diagnosis of ASD. The ASD rates were 11.30% and 0.92% for younger siblings of older affected and unaffected siblings, respectively (aRR: 14.27; 95% confidence interval, 11.41–17.83). This association remained after adjusting for potential confounding factors. Race/ethnicity- and gestational age-specific analyses revealed a positive association of similar magnitude across groups. Risk remained higher in younger boys than girls regardless of the sex of affected older siblings. Conclusion: The findings of this study suggest that the risk of ASD in younger siblings is higher if the older sibling has ASD. The risk of ASD in younger siblings of older affected siblings was comparable across gestational age at birth and childs race/ethnicity groups. However, risk remains higher for boys. This study contributes to a better understanding of the influence of race/ethnicity, sex, and gestational age at birth in identifying children at higher risk of ASD.