Joël Girouard

Early occurrence of metabolic syndrome after hypertension in pregnancy.

OBJECTIVE: The objective of the present study was to evaluate the cardiovascular risk profile and the prevalence of metabolic syndrome among women with a history of pregnancy-induced hypertension (PIH). METHODS: From a cohort of 3,799 nulliparous women prospectively recruited between 1989 and 1997, we performed an observational study on 168 case-control pairs 7.8 years after delivery. Participants were scheduled for a visit with a research nurse to evaluate their cardiovascular risk profile using a questionnaire, anthropometric measurements and blood specimen analysis. RESULTS: One hundred sixty-eight women with prior PIH (105 with gestational hypertension and 63 with preeclampsia) and 168 controls matched for age and year of index delivery were evaluated. The women with PIH (34.6 ± 4.4 years) were more obese and had higher systolic (115 mm Hg versus 108 mm Hg) and diastolic (75 mm Hg versus 70 mm Hg) blood pressures (P < .001) than the 168 controls (35.1 ± 4.5 years). They had lower high-density lipoprotein cholesterol level (1.30 mmol/L versus 1.42 mmol/L; P < .001), increased fasting blood glucose concentration (5.2 mmol/L versus 5.0 mmol/L; P = .002), and higher insulin levels (119 versus 91 pmol/L; P < .001). The prevalence of the metabolic syndrome was higher in the PIH group (unadjusted odds ratio = 4.9; 95% confidence interval 2.1–10.9) compared with controls, even after adjustment for confounders (adjusted odds ratio = 3.6; 95% confidence interval 1.4 –9.0). CONCLUSION: In white women in their mid-30s, the prevalence of the metabolic syndrome is 3- to 5-fold increased in those with a history of PIH in their first pregnancy. This emphasizes the importance of long-term follow-up assessment for cardiovascular risk factors in these women. LEVEL OF EVIDENCE: II-2

Previous Hypertensive Disease of Pregnancy Is Associated With Alterations of Markers of Insulin Resistance

Insulin resistance syndrome has been observed in women with hypertensive disease of pregnancy, but few studies evaluated the presence of the syndrome a few years after delivery. The objective of this study was to evaluate the presence of insulin resistance and its metabolic alterations in these women compared with those who had a normal pregnancy. We performed an observational study in 168 women with previous hypertensive disease of pregnancy and 168 control subjects with normal pregnancy contacted, on average, 7.8 years after their first delivery (mean age: 34.8 years). Complete blood lipid profile, insulin, glucose, homocysteine, adipokins, and markers of inflammation were measured. Also, an oral glucose tolerance test was performed in 146 case and 135 control subjects. Case subjects were more overweight compared with control subjects. We found significantly lower high-density lipoprotein cholesterol and adiponectin levels and higher apolipoprotein (apo) apoB/apoA1 ratio, homocysteine, leptin, and insulin levels among case subjects compared with control subjects (P≤0.004). Also, case subjects were more insulin resistant in the basal state estimated by homeostasis assessment model 2, as well as in the nonbasal state as estimated by insulin sensitivity indices calculated from the oral glucose tolerance test. Finally, in a multivariate regression model, leptin, apoB/apoA1 ratio, waist circumference, adiponectin, and free fatty acids explained 40% of homeostasis assessment model 2 variance. Young women with previous hypertensive disease of pregnancy show signs of insulin resistance within the first decade after delivery. These findings suggest that insulin resistance may be the link between hypertensive disease of pregnancy and increased cardiovascular risk later in life.

Pathophysiology and maternal biologic markers of preeclampsia.

Preeclampsia—increased blood pressure and proteinuria appearing after the twentieth week of pregnancy—is a major cause of materal and neonatal morbidity, leading to iatrogenic prematurity. Several lines of evidence suggest that the disorder is owing to diminished invasion of spiral arteries by trophoblastic cells, followed by reduced perfusion of the fetoplacental unit and oxidative stress. These alterations, in the presence of maternal predisposition, lead to endothelial dysfunction and occurrence of the clinical syndrome of preeclampsia (multisystemic lesions). Although the pathophysiology of preeclampsia is still unknown, progress has been made during the past 10 yr, and the early identification of at-risk women with the use of biochemical; ultrasonographic; and, more recently, genetic susceptibility markers has been the subject of intense research. In the present review, markers of maternal predisposition, placental implantation, oxidative stress, vasomotor regulation, and endothelial dysfunction are investigated as candidate markers in the early prediction of preeclampsia. Unfortunately, at the present time, no marker has been proven to have a clinically useful predictive performance in the general pregnant population, and, therefore, more research in that area is warranted.

Population prevalence of APOE, APOC3 and PPAR-α mutations associated to hypertriglyceridemia in French Canadians

AbstractHypertriglyceridemia (HTG) is known as a common metabolic disorder associated with increased production, decrease catabolism and/or decreased hepatic uptake of triglyceride (TG)-rich particles. We assessed, in the Québec City population, the allele frequency and haplotype distributions of mutations in genes related to HTG, such as the apolipoprotein E (APOE) (C112R and C158R), the apolipoprotein CIII (APOC3) (C-482T and C3238G) and the peroxisome proliferator-activated receptor alpha (PPARα) (L162V) genes. A total of 938 anonymous unlinked newborns from the metropolitan Québec City area have been genotyped. Allele frequencies observed in the Québec City population differed from known frequencies determined in other Caucasian populations. The co-transmitted allele distribution between the two-marker genotypes APOE/APOC3(C3238G) and APOC3(C-482T)/PPARα(L162V) presented a weak deviation from the assumption of genetic independence. Also, we observed a non-independent distribution of the T-482/G3238 allele combinations within the APOC3 gene, suggesting strong linkage disequilibrium between the C-482T and C3238G polymorphisms. Moreover, comparisons of allele frequencies observed in the population of Québec City to those obtained in other Caucasian populations suggested that the population of Québec City may be at a lower risk of developing HTG due to APOE, APOC3 and PPARα genetic variants. However, the strong linkage disequilibrium and the two-marker genotype distributions observed in the APOC3 gene suggest that these two variants may functionally interact in the Québec City population.

The combination of ApoCIII, hepatic lipase and hormono sensitive lipase gene polymorphisms suggests an association with susceptibility to gestational hypertension.

AbstractDyslipidemia and insulin resistance contribute to the endothelial cell dysfunction in hypertensive disorders of pregnancy (HDP) and increase the long-term risk of cardiovascular disease (CVD). The genes linking susceptibility to gestational hypertension (GH) and/or preeclampsia (PE) to the long-term risk of CVD are still unknown. We evaluated the potential association between 14 polymorphisms from six genes involved in lipid metabolism and insulin action and the risk of HDP: namely the lipoprotein lipase (LPL), hepatic lipase (LIPC), hormone sensitive lipase (LIPE), cholesteryl ester transfer protein (CETP), ApoCIII and ApoE gene polymorphisms. Overall, 169 women with HDP [proteinuria (PE) and gestational hypertension without proteinuria (GH)] and 169 controls matched for age and year of delivery were genotyped. Homozygosity of the −514T allele of the −514C > T polymorphism (LIPC gene) decreased the risk of GH (OR = 0.17, CI95: 0.02-0.76), while there were more −60G carriers of the −60C > G LIPE gene polymorphism (OR = 3.51, CI95:1.02-12.10) among GH cases, but not in PE cases. The common ApoCIII two-locus −482CC/3238CC genotype was lower in women with GH compared with controls (OR = 0.53, CI95: 0.3-0.9). The combined frequency of at-risk genotypes was higher in cases of GH compared with controls [one at-risk genotype: OR = 3.38 (95% CI: 0.48-41.8); two or more at-risk genotypes: OR = 7.14 (95% CI: 1.21-92.3, P = 0.01)], suggesting a gene-dose effect. We conclude that the combined effect of LIPC, LIPE and ApoCIII gene polymorphisms may increase the likelihood of GH, but seemingly not of PE.

Absence of association between serum folate and preeclampsia in women exposed to food fortification.

OBJECTIVE: To evaluate serum folate concentration early in pregnancy and any association with hypertensive disorders of pregnancy in a population exposed to folic acid supplementation and food fortification. METHODS: This is a nested case–control study based on a prospective cohort of 7,929 pregnant women recruited in the Quebec City metropolitan area, including 214 participants who developed a hypertensive disorder of pregnancy and 428 normotensive participants in the control group matched for parity, multiple pregnancy, smoking status, gestational, and maternal age at inclusion, and duration of blood sample storage. Serum folate levels were measured at a mean of 14 weeks of gestation. RESULTS: More than 98% of the participants took folic acid or multivitamins before the end of the first trimester. Mean serum folate levels were accordingly high and there were no differences between women who further developed a hypertensive disorder of pregnancy compared with women in the control group (60.1 nmol/L compared with 57.9 nmol/L; P=.51). The proportion of participants with serum folate below the 10th percentile (less than 22.3 nmol/L) of age-matched women in our outpatient population was similar between groups (P=.66) and no participant had levels generally defined as folate deficiency (less than 10 nmol/L). CONCLUSION: In a general cohort of pregnant women benefiting from a national policy of folic acid food fortification combined with a high adherence to folic acid supplementation, serum folate levels are high and do not differ between women who develop a hypertensive disorder of pregnancy and women who remain normotensive. Further supplementation with higher doses is unlikely to be beneficial in such populations. LEVEL OF EVIDENCE: II

Early prediction of gestational diabetes: a practical model combining clinical and biochemical markers.

Abstract Background: Gestational diabetes (GDM) is usually diagnosed late in pregnancy, precluding early preventive interventions. This study aims to develop a predictive model based on clinical factors and selected biochemical markers for the early risk assessment of GDM. Methods: Based on a prospective cohort of 7929 pregnant women from the Quebec City metropolitan area, a nested case-control study was performed including 264 women who developed GDM. Each woman who developed GDM was matched with two women with normal glycemic profile. Risk prediction models for GDM and GDM requiring insulin therapy were developed using multivariable logistic regression analyses, based on clinical characteristics and the measurement of three clinically validated biomarkers: glycated hemoglobin (HbA1c), sex hormone binding globulin (SHBG) and high-sensitivity C-reactive protein (hsCRP) measured between 14 and 17 weeks of gestation. Results: HbA1c and hsCRP were higher and SHBG was lower in women who developed GDM (p<0.001). The selected model for the prediction of GDM, based on HbA1c, SHBG, BMI, past history of GDM, family history of diabetes and soft drink intake before pregnancy yielded an area under the ROC curve (AUC) of 0.79 (0.75–0.83). For the prediction of GDM requiring insulin therapy, the selected model including the same six variables yielded an AUC of 0.88 (0.84–0.92) and a sensitivity of 68.9% at a false-positive rate of 10%. Conclusions: A simple model based on clinical characteristics and biomarkers available early in pregnancy could allow the identification of women at risk of developing GDM, especially GDM requiring insulin therapy.

Mid-Trimester Maternal Serum AFP and hCG as Markers of Preterm and Term Adverse Pregnancy Outcomes

OBJECTIVE To evaluate the predictive values of mid-trimester serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) for preterm and term placenta-mediated adverse pregnancy outcomes (PMAPOs). METHODS We extracted data for nulliparous women with a singleton pregnancy without aneuploidy or lethal fetal anomalies from a prospective cohort study. Maternal serum AFP and hCG measured between 13 and 17 weeks of gestation and expressed as multiples of the median (MoM) for gestational age were compared between women who developed a PMAPO (preeclampsia, intrauterine growth restriction, fetal death) before term or at term and women who did not develop any of these complications. RESULTS Among 3466 nulliparous women, maternal serum AFP and hCG levels were available in 2110 and 2125 cases, respectively. Women who developed a PMAPO before term had a higher median level of serum AFP (1.4 vs. 1.1 MoM; P < 0.01) and hCG (1.3 vs. 1.1 MoM; P < 0.01) than controls. A serum hCG > 2.0 MoM was associated with a higher risk of PMAPO before term (RR 4.6; CI 95% 2.3 to 9.1) but had no impact on the risk of PMAPO at term (RR 1.1; CI 95% 0.7 to 1.7). Maternal serum AFP > 2.0 MoM was also associated with a significant increase in the risk of preterm PMAPO (RR 3.9; CI 95% 1.6 to 9.8) but not term PMAPO (RR 1.2; CI 95% 0.6 to 2.3). CONCLUSION Maternal serum AFP or hCG > 2.0 MoM increases the risk of preterm PMAPO but not term PMAPO in our population. We suggest that women with elevated serum AFP or hCG should receive standard pregnancy care once they have reached 37 weeks of gestation if fetal growth is in the normal range.

Pregnancy Disorders and Perinatal Outcomes

Embryo implantation is a complex process; primary step in implantation is the initiation of dialogue between free floating blastocyst and the receptive endometrium. This is followed by a stable adhesion of the blastocyst anchors to the endometrial basal lamina and stromal extracellular matrix. The last step is invasion of the embryo through the luminal epithelium and its basal lamina into the uterine stroma. Successful embryo implantation depends up on number of factors like steroid hormones (progesterone, estrogen), Cyclooxygenases, prostaglandins, cytokines, growth factors, transcription factors (HOXA-10 and HOXA-11), and adhesion molecules (integrins, selectins, cadherins, mucins) and receptive endometrium. Importantly, there is timely regulation of these factors and their cross talk which mediates the implantation process. Blastocyst is unable to implant successfully if there is deregulation in any of these factors leading to pregnancy loss. In this chapter we reviewed the information available till date to provide possible causes of implantation failure and its positive outcomes.