Maternal cardiovascular disease after twin pregnancies complicated by hypertensive disorders of pregnancy: a population-based cohort study

Background:People whose singleton pregnancy is affected by hypertensive disorders of pregnancy (HDP) are at risk of future cardiovascular disease. It is unclear, however, whether this association can be extrapolated to twin pregnancies. We aimed to compare the association between HDP and future cardiovascular disease after twin and singleton pregnancies.Methods:We conducted a population-based retrospective cohort study that included nulliparous people in Ontario, Canada, 1992–2017. We compared the future risk of cardiovascular disease among pregnant people from the following 4 groups: those who delivered a singleton without HDP (referent) and with HDP, and those who delivered twins either with or without HDP.Results:The populations of the 4 groups were as follows: 1 431 651 pregnant people in the singleton birth without HDP group; 98 631 singleton birth with HDP; 21 046 twin birth without HDP; and 4283 twin birth with HDP. The median duration of follow-up was 13 (interquartile range 7–20) years. The incidence rate of cardiovascular disease was lowest among those with a singleton or twin birth without HDP (0.72 and 0.74 per 1000 person-years, respectively). Compared with people with a singleton birth without HDP, the risk of cardiovascular disease was highest among those with a singleton birth and HDP (1.47 per 1000 person-years; adjusted hazard ratio [HR] 1.81 [95% confidence interval (CI) 1.72–1.90]), followed by people with a twin pregnancy and HDP (1.07 per 1000 person-years; adjusted HR 1.36 [95% CI 1.04–1.77]). The risk of the primary outcome after a twin pregnancy with HDP was lower than that after a singleton pregnancy with HDP (adjusted HR 0.74 [95% CI 0.57–0.97]), when compared directly.Interpretation:In a twin pregnancy, HDP are weaker risk factors for postpartum cardiovascular disease than in a singleton pregnancy.

Cardiovascular disease has been shown to be the leading cause of death among women.^1–3 Classic risk factors for cardiovascular disease include obesity, diabetes mellitus, hypertension and family history of cardiovascular disease. ³ More recently, an association has been established between a history of hypertensive disorders of pregnancy (HDP) — gestational hypertension and pre-eclampsia — and future risk of cardiovascular disease.^1,4–11 Consequently, some recommend using a history of HDP for cardiovascular disease risk stratification in women.^3,12The leading hypothesis for the pathogenesis of HDP is that it results from abnormal placentation due to impaired trophoblast invasion,^13–16 resulting in reduced placental perfusion.^17–19 This, in turn, leads to abnormal secretion of the angiogenic factors soluble FMS-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng),²⁰ which induce endothelial dysfunction and the clinical manifestations of HDP.^19,21–24 The mechanisms underlying the association between HDP and future cardiovascular disease are under debate.²⁵ One hypothesis is that HDP are merely a marker of underlying subclinical or clinical vascular risk factors that predispose a person to both HDP and future cardiovascular disease.A person who is pregnant with twins is at about 3–4 times higher risk of HDP than a person with a singleton pregnancy,^26–33 with rates of 14% and 5%, respectively.³⁴ The higher risk of HDP in twin pregnancies may be due to higher circulating sFlt1 and sEng owing to greater placental mass in twin pregnancies, ^35–37 and less related to the classic vascular risk factors for HDP in a singleton pregnancy. Therefore, a logical question is whether the established higher risk of future cardiovascular disease after singleton pregnancies with HDP also occurs in twin pregnancies with HDP. Limited data are available to answer this question.³⁸ In the current study, we aimed to test the hypothesis that the association between HDP and future cardiovascular disease is less pronounced in twin versus singleton pregnancies.     

Recognition of asymptomatic hypercholanemia of pregnancy: Different clinical features,fetal outcomes and bile acids metabolism from intrahepatic cholestasis of pregnancy

ObjectiveTo explore the clinical features, fetal outcomes and serum bile acids (BAs) metabolism in asymptomatic hypercholanemia of pregnancy (AHP), as well as the comparison with those in intrahepatic cholestasis of pregnancy (ICP) and normal pregnancies.MethodsA study containing 676 pregnant women was performed to investigate the clinical informations, routine biochemical features and obstetric outcomes of AHP by the comparison with ICP and normal pregnancies. Within the study subjects, 203 pregnant women received prospective determination for 55 serum individual BAs based on a validated UPLC-QTOF-MS/MS method. The differences in clinical features and serum BAs metabolism among the three groups were then investigated.ResultsThe risk of adverse fetal outcomes in AHP (28.3%) was significantly higher than that in normal pregnancies (8.9%, p < 0.001), but lower than that in ICP group (52.1%, p < 0.001). Multivariate statistics analysis indicated a distinctive serum BAs metabolic profiling among the three groups (PLS-DA, R²Y = 0.580, Q² = 0.537). Levels of serum BAs especially for deoxycholic acid species were found remarkably elevated in AHP as compared to those in ICP.ConclusionsAHP group had distinguished clinical features and serum BAs metabolism as compared to ICP group and normal pregnancies.     

Metabolomic profiling of maternal hair suggests rapid development of intrahepatic cholestasis of pregnancy

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a common maternal liver disease; development can result in devastating consequences, including sudden fetal death and stillbirth. Currently, recognition of ICP only occurs following onset of clinical symptoms.

Objective

Investigate the maternal hair metabolome for predictive biomarkers of ICP.

Methods

The maternal hair metabolome (gestational age of sampling between 17 and 41 weeks) of 38 Chinese women with ICP and 46 pregnant controls was analysed using gas chromatography–mass spectrometry.

Results

Of 105 metabolites detected in hair, none were significantly associated with ICP.

Conclusion

Hair samples represent accumulative environmental exposure over time. Samples collected at the onset of ICP did not reveal any metabolic shifts, suggesting rapid development of the disease.

     

Low serum selenium concentration and glutathione peroxidase activity in intrahepatic cholestasis of pregnancy.

Serum selenium concentrations were found to be significantly lower in women with intrahepatic cholestasis of pregnancy than in women with normal pregnancies during the last trimester of pregnancy and post partum. The activity of the selenoenzyme glutathione peroxidase had a significant positive correlation with selenium concentration and it was also significantly lower in women with the disease. These findings suggest that selenium deficiency and reduced glutathione peroxidase activity are associated with the aetiopathogenesis of intrahepatic cholestasis of pregnancy.     

妊娠肝内胆汁淤积症胎儿猝死发病机制的研究进展

妊娠肝内胆汁淤积症（ICP）妊娠晚期胎儿猝死,难以预料和准确监测,具有高风险性。目前其机制不明。孕妇和胎儿高胆汁酸水平对胎盘功能的影响和对胎儿的损伤是当前研究的主要方向。特别是一系列胆汁酸对心肌细胞毒性作用的实验,提示胆汁酸对胎儿心脏的毒性作用可能是引起胎儿猝死的重要原因。     

The role of phosphatidylethanolamine methyltransferase in a mouse model of intrahepatic cholestasis

Intrahepatic cholestasis eventually leads to liver failure. We report here a condition that decreases liver damage in intrahepatic cholestasis based on a mouse model that lacks multiple drug resistant protein 2 (ABCB4). We found that lack of phosphatidylethanolamine N-methyltransferase (PEMT) decreased liver damage in Abcb4(-/-) mice caused by exposure of the liver to excess bile acids. The protective effect was not related to hepatic ratio of phosphatidylcholine to phosphatidylethanolamine or the level of cholesterol. The decreased concentration of bile acids in liver was related to impaired re-absorption of bile acids in intestine and increased disposal of bile acids in feces in Abcb4(-/-)/Pemt(-/-) mice as compared to Abcb4(-/-) mice. PEMT deficiency affected intestinal Na(+) absorption resulting in an impaired Na(+) concentration gradient along the length of the small intestine and abnormal absorption of bile acids mediated by apical sodium-dependent bile acid transporter (ASBT). The findings of this study suggest that inhibition of PEMT and/or reduction of intestinal sodium concentration may be helpful in attenuating liver damage and prolonging hepatic function in intrahepatic cholestasis.     

High-performance liquid chromatography-tandem mass spectrometry for the analysis of bile acid profiles in serum of women with intrahepatic cholestasis of pregnancy

A simple, sensitive, and specific high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the analysis of the bile acid profile has been developed. Fifteen bile acids, including free and conjugated bile acids, were separated and detected by HPLC-MS/MS. The MS detection was performed by electrospray ionization (ESI) in negative ion mode. Quantification was achieved in multiple reaction monitoring (MRM) mode with external standard curve methods. Total analysis time was 15 min for one sample including re-equilibration time of the column. The assay was linear in the range 0.02-100.0 micromol/L with correlation coefficients of standard curves for all bile acids better than 0.999. The detection limits ranged from 0.001 to 0.006 micromol/L for different bile acids. The precisions for each bile acid were CVs<3.8% for within-day and CVs<6.1% for between-day. The average recoveries for all bile acids studied were in the range of 86-110.0%. The developed method was applied to the analysis of clinic samples consisting of 53 women with healthy pregnancies and 43 women with intrahepatic cholestasis of pregnancy (ICP). The results revealed that the bile acid profile was markedly different between women with ICP and women with healthy pregnancies.     

A prospective cohort study of pregnancy risk factors and birth outcomes in Aboriginal women

Background

Aboriginal women have been identified as having poorer pregnancy outcomes than other Canadian women, but information on risk factors and outcomes has been acquired mostly from retrospective databases. We compared prenatal risk factors and birth outcomes of First Nations and Métis women with those of other participants in a prospective study.

Methods

During the 12-month period from July 1994 to June 1995, we invited expectant mothers in all obstetric practices affiliated with a single teaching hospital in Edmonton to participate. Women were recruited at their first prenatal visit and followed through delivery. Sociodemographic and clinical data were obtained by means of a patient questionnaire, and microbiological data were collected at 3 points during gestation: in the first and second trimesters and during labour. Our primary outcomes of interest were low birth weight (birth weight less than 2500 g), prematurity (birth at less than 37 weeks'' gestation) and macrosomia (birth weight greater than 4000 g).

Results

Of the 2047 women consecutively enrolled, 1811 completed the study through delivery. Aboriginal women accounted for 70 (3.9%) of the subjects who completed the study (45 First Nations women and 25 Métis women). Known risk factors for adverse pregnancy outcome were more common among Aboriginal than among non-Aboriginal women, including previous premature infant (21% v. 11%), smoking during the current pregnancy (41% v. 13%), presence of bacterial vaginosis in midgestation (33% v. 13%) and poor nutrition as measured by meal consumption. Although Aboriginal women were less likely than non-Aboriginal women to have babies of low birth weight (odds ratio [OR] 1.46, 95% confidence interval [CI] 0.52–4.15) or who were born prematurely (OR 1.45, 95% CI 0.57–3.72) and more likely to have babies with macrosomia (OR 2.04, 95% CI 1.03–4.03), these differences were lower and statistically nonsignificant after adjustment for smoking, cervicovaginal infection and income (adjusted OR for low birth weight 0.85, 95% CI 0.19–3.78; for prematurity 0.90, 95% CI 0.21–3.89; and for macrosomia 2.12, 95% CI 0.84-5.36).

Interpretation

After adjustment for potential confounding factors, we found no statistically significant relation between Aboriginal status and birth outcome.It is generally recognized that Aboriginal women experience poorer birth outcomes than other North American women, including higher rates of stillbirth,¹ low-birth-weight infants^1,2,3 and prematurity.^2,3 Although significant efforts have been made to reduce Aboriginal infant mortality rates, these rates remain higher than for other infants in both Canada⁴ and the United States.⁵ Little is known about the reasons for differences in birth outcomes, although social, economic, medical and prenatal care factors have been suggested. Recent publications, based on retrospective analyses of large databases, have confirmed disparities in birth outcomes between Aboriginal and all other groups,^3,6,7 but there is a paucity of prospective data. In addition, although the term “Aboriginal” refers to a heterogeneous population comprising First Nations people, Métis and Inuit, there are few comparisons between specific Aboriginal groups or of Aboriginal groups with the general population.We report here the results of a prospective study in a general obstetric population, comparing birth outcomes and known pregnancy risk factors of Aboriginal women with those of non-Aboriginal Canadian women. In addition to well-recognized socioeconomic and reproductive risk factors, we investigated the prevalence of maternal cervicovaginal infections, which have been increasingly linked to prematurity.^8,9     

Low activity of gamma-glutamyl transpeptidase in serum of acute intrahepatic cholestasis.

Low gamma-glutamyl transpeptidase (gamma-GTP) activity in serum was observed in 11 patients with acute intrahepatic cholestasis (cholestatic hepatitis and fulminant hepatitis), despite a marked increase in bilirubin levels. Inhibitors of gamma-GTP were not detected in sera of these patients. Their gamma-GTP levels in the liver were significantly higher than those in chronic liver diseases. An electrophoretic study of liver gamma-GTP in acute intrahepatic cholestasis showed the same mobility as in chronic liver diseases. These results suggest that the low serum gamma-GTP activity in acute intrahepatic cholestasis is due to factors inhibiting the release of the enzyme from the liver.     

Alterations of high density lipoproteins in experimental intrahepatic cholestasis in the rat induced by administration of alpha-naphthylisothiocyanate

It has previously been reported that abnormally enlarged high density lipoproteins (HDL) appear in rats with extrahepatic cholestasis induced by ligation of the common bile duct. To see whether similar changes in HDL occur in intrahepatic cholestasis in rats, we studied HDL alterations in rats treated with alpha-naphthylisothiocyanate (ANIT), which is known to produce a cholestatic response in rats similar to intrahepatic cholestasis in man. Findings were obtained which indicated changes in HDL similar to those in bile duct-ligated rat serum: HDL from ANIT-treated rats were separated into two subfractions, enlarged particles and smaller ones, on Bio-Gel A5m column chromatography. In electron micrographs, the two subfractions appeared spherical and the diameters of the enlarged particles and the other ones were 15.0 +/- 2.6 nm and 11.5 +/- 2.2 nm, respectively. Both subfractions showed slow alpha-mobility in agarose gel electrophoresis. The enlarged HDL had apoE as their major apoprotein, while apoA-I was the major apoprotein in the other HDL subfraction. The enlarged HDL contained less protein and more cholesterol than the other HDL subfraction. The two HDL subfractions were also separated by heparin-Sepharose affinity chromatography.     

Prevention by dietary (n-6) polyunsaturated phosphatidylcholines of intrahepatic cholestasis induced by cyclosporine A in animals

Previous findings showed that dietary (n-6) polyunsaturated phosphatidylcholines (vegetable lecithin) could efficiently prevent intrahepatic cholestasis induced by cyclosporine A in rats. Mechanistic studies showed that expressions in rat liver of Na(+), K(+)-ATPase, Ca(2+), Mg(2+)-ATPase and F-actin were both decreased by drug administration and both enhanced by (n-6) lecithin enriched diet. There is a possible direct effect of phosphatidylcholines, vectors of polyunsaturated fatty acids provided by the metabolism of the dietary lecithin, on the aforesaid hepatic parameters. Such modulations by drug and diet result in reversed modifications of membrane composition and fluidity. Final outcome is decreased and enhanced bile lipid secretion by cyclosporine and vegetable lecithin enriched diet respectively. Moreover, we advance the hypothesis of a bypass process including a separate and functional actin-independent way for the non micellar and phospholipid-dependent secretion of bile lipids. The relationships between the ATPases, the microfilament components such as F-actin and the different transporters still remain to be clarified. Furthermore, one can speculate on beneficial effects in humans of diets enriched in vegetable lecithins that might prevent cholestasis induced by cyclosporine A.     

A half-yearly aspect of circulating melatonin in pregnancies complicated by intrauterine growth retardation

In investigating mechanisms underlying intrauterine growth retardation (IUGR), circulating melatonin and cortisol were radioimmunoassayed. Blood samples were collected every 4 hours during 24 hours on a strict 24-hour standardized routine in hospital from two groups of women in their third trimester of pregnancy. One group consisted of 14 healthy, uncomplicated pregnancies (HAGA); the other group consisted of 11 pregnancies complicated by intrauterine growth retardation (IUGR) confirmed at birth. The circadian characteristics of melatonin and cortisol were assessed for each woman and compared between the two groups by analyses of variance for repeated measures and by parameter tests based on the cosinor. Since a circasemiannual (about half-yearly) component prominently characterizes body weight and length at birth of children with birth characteristics below usual norms, the circadian characteristics of melatonin and cortisol were also analyzed transversely (across women within each group). The 24-hour average and the 24-hour and 12-hour amplitudes of melatonin of women in the IUGR, but not in the HAGA group, were indeed found to be modulated by an about half-yearly component. This study confirms the circadian rhythmicity of melatonin in healthy pregnant women and extends the finding to pregnancies complicated by IUGR, uncovering about half-yearly changes in melatonin in women with IUGR, thereby extending results obtained in healthy non-pregnant women and men. These variations may reflect influences from geomagnetic disturbances also characterized by a prominent half-yearly pattern, to which the pineal has been shown to be sensitive.