Lipid metabolism during pregnancy: consequences for mother and child.

PURPOSE OF REVIEW: Accommodating fetal growth and development, women undergo multiple physiological changes during pregnancy. In recent years, several studies contributed to the accumulating evidence about the impact of gestational hyperlipidemia on cardiovascular risk for mother and child. This review aims to provide a comprehensive overview of the current research on lipid profile alterations during pregnancy and its associated (cardiovascular) outcomes for mother and child from a clinical perspective. RECENT FINDINGS: In a normal pregnancy, total and LDL-cholesterol levels increase by approximately 30-50%, HDL-cholesterol by 20-40%, and triglycerides by 50-100%. In some women, for example, with familial hypercholesterolemia (FH), a more atherogenic lipid profile is observed. Dyslipidemia during pregnancy is found to be associated with adverse (cardiovascular) outcomes for the mother (e.g. preeclampsia, gestational diabetes, metabolic syndrome, unfavorable lipid profile) and for the child (e.g. preterm birth, large for gestational age, preatherosclerotic lesions, unfavorable lipid profile). SUMMARY: The lipid profile of women during pregnancy provides a unique window of opportunity into the potential future cardiovascular risk for mother and child. Better knowledge about adverse outcomes and specific risk groups could lead to better risk assessment and earlier cardiovascular prevention. Future research should investigate implementation of gestational screening possibilities.

Women, lipids, and atherosclerotic cardiovascular disease: a call to action from the European Atherosclerosis Society.

Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women.

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance.

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.

Unexpected gaps in knowledge of familial hypercholesterolaemia among Dutch general practitioners.

BACKGROUND: Familial hypercholesterolaemia (FH) warrants early diagnosis to prevent premature atherosclerotic cardiovascular disease (CVD). However, underdiagnosis and undertreatment of FH persist. This study aimed to assess the knowledge and practice of FH care among general practitioners (GPs) in the Netherlands. METHODS: An internationally standardised, online questionnaire was sent to Dutch GPs between February 2021 and July 2022. The survey assessed knowledge and awareness of FH, encompassing general familiarity, awareness of management guidelines, inheritance, prevalence, CVD risk, and clinical practice related to FH. Comparative analysis was performed using data on primary care physicians from Western Australia, the Asia-Pacific region and the United Kingdom. RESULTS: Of the 221 participating GPs, 62.4% rated their familiarity with FH as above average (score > 4 on a 1-7 scale), with 91.4% considering themselves familiar with FH treatment and referral guidelines. Correct identification of the FH definition, typical lipid profile, inheritance pattern, prevalence and CVD risk was reported by 83.7%, 87.8%, 55.7%, 19.5%, and 13.6% of the respondents, respectively. Of the participants, 58.4% answered fewer than half of the 8 knowledge questions correctly. Dutch GPs reported greater FH familiarity and guideline awareness compared with their international counterparts but exhibited similar low performance on FH knowledge questions. CONCLUSION: Despite the Netherlands' relatively high FH detection rate, substantial knowledge gaps regarding FH persist among Dutch GPs, mirroring global trends. Enhanced FH education and awareness in primary care are imperative to improve FH detection and ensure adequate treatment. Targeting the global suboptimal understanding of FH might require international efforts.

Sex Differences in Familial Hypercholesterolemia.

PURPOSE OF REVIEW: This review aims to summarize the existing research on sex differences in familial hypercholesterolemia (FH) across the lifespan. RECENT FINDINGS: From childhood onward, total- and low-density lipoprotein cholesterol (LDL-C) levels in girls are higher than those in boys with FH. By the age of 30 years, women with FH have a higher LDL-C burden than men. In adulthood, women are diagnosed later than men, receive less lipid-lowering treatment, and consequently have higher LDL-C levels. An excessive atherosclerotic cardiovascular disease risk is reported in young female compared to male FH patients. The periods of pregnancy and breastfeeding contribute to treatment loss and increased cholesterol burden. Earlier initiation of treatment, especially in girls with FH, and lifelong treatment during all life stages are important. Future research should aim to recruit both women and men, report sex-specific data, and investigate the impact of the female life course on cardiovascular outcomes. Future guidelines should include sex-specific aspects.

Sexual functioning more than 15 years after premenopausal risk-reducing salpingo-oophorectomy.

BACKGROUND: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure 1 to 3 years after a premenopausal oophorectomy. However, the long-term effects of premenopausal oophorectomy on sexual functioning are unknown. OBJECTIVE: This study aimed to study long-term sexual functioning in women at increased familial risk of breast or ovarian cancer who underwent a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group) or after the age of 54 years (postmenopausal group). Subgroup analyses were performed in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy. STUDY DESIGN: Between 2018 and 2021, 817 women with a high familial risk of breast or ovarian cancer from an ongoing cohort study were invited to participate in our study. Because of a large difference in age in the study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual functioning between the groups to 368 women who were 60 to 70 years old at completion of the questionnaire (226 in the premenopausal group and 142 in the postmenopausal group). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy, we compared the sexual functioning between women in the early premenopausal group (n=151) and women in the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses, adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes or no), and body image. RESULTS: Mean times since risk-reducing salpingo-oophorectomy were 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (P<.001). The mean age at questionnaire completion was 62.7 years in the premenopausal group, compared with 67.0 years in the postmenopausal group (P<.001). Compared with 48.9% of women in the postmenopausal group, 47.4% of women in the premenopausal group were still sexually active (P=.80). Current sexual pleasure scores were the same for women in the premenopausal group and women in the postmenopausal group (mean pleasure score, 8.6; P=.99). However, women in the premenopausal group more often reported substantial discomfort than women in the postmenopausal group (35.6% vs 20.9%; P=.04). After adjusting for confounders, premenopausal risk-reducing salpingo-oophorectomy was associated with substantially more discomfort during sexual intercourse than postmenopausal risk-reducing salpingo-oophorectomy (odds ratio, 3.1; 95% confidence interval, 1.04-9.4). Moreover, after premenopausal risk-reducing salpingo-oophorectomy, more severe complaints of vaginal dryness were observed (odds ratio, 2.6; 95% confidence interval, 1.4-4.7). Women with a risk-reducing salpingo-oophorectomy before the age of 41 years reported similar pleasure and discomfort scores as women with a risk-reducing salpingo-oophorectomy between ages 41 and 45 years. CONCLUSION: More than 15 years after premenopausal risk-reducing salpingo-oophorectomy, the proportion of sexually active women was comparable with the proportion of sexually active women with a postmenopausal risk-reducing salpingo-oophorectomy. However, after a premenopausal risk-reducing salpingo-oophorectomy, women experienced more vaginal dryness and more often had substantial sexual discomfort during sexual intercourse. This did not lead to less pleasure with sexual activity.

Long-term effects of premenopausal risk-reducing salpingo-oophorectomy on cognition in women with high familial risk of ovarian cancer: A cross-sectional study.

OBJECTIVE: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO. DESIGN: A cross-sectional study with prospective follow-up, nested in a nationwide cohort. SETTING: Multicentre in the Netherlands. POPULATION OR SAMPLE: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment. METHODS: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression. MAIN OUTCOME MEASURES: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO. RESULTS: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1-3.1) and multitasking (OR 1.9, 95% CI 1.1-3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years). CONCLUSIONS: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.

Establishing the relationship between familial dysbetalipoproteinemia and genetic variants in the APOE gene.

Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol-enriched remnant lipoproteins. FD is usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow-up, and family counseling.

Sex steroids and sex steroid-binding globulin levels amongst middle-aged and elderly men and women from general population.

BACKGROUND AND AIMS: Availability of age- and sex-specific reference values for sex steroids and sex steroid-binding globulin (SHBG) levels allows for appropriate interpretation of research findings and their clinical applications. We report the sex-specific distribution and reference levels of sex steroids, including total estradiol, total testosterone and (calculated) free androgen index (cFAI), SHBG and other androgens dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione across age. METHODS: Using data from 3291 participants from the prospective population-based Rotterdam Study (2006-2008), we visualised the distribution of sex steroids and SHBG levels by calculating and depicting the 5th, 25th, 50th, 75th and 95th percentiles per year and per age-year across 5-year age bands to provide reference value ranges in men and women. Total estradiol and SHBG were measured using automated immunoassay and androgens using liquid chromatography-mass spectrometry (LC-MS/MS). RESULT: Mean age was 56.8 (range 45.6-79.9) years in men and 56.9 (range 45.7-79.9) years in women. Amongst men, total estradiol and SHBG showed an increasing trend from 45 years onwards. In women, total estradiol and SHBG showed a decreasing trend from 45 years until the age of 60. From 60 years onwards, SHBG showed an increasing trend. For total testosterone, a clear declining trend was observed amongst men but not women. Other androgens showed a similar decreasing trend in both sexes from 45 years onwards. DISCUSSION AND CONCLUSION: Our study underlines sex-specific trends in sex steroids and SHBG levels with ageing. This warrants taking into account sex- and age-specific reference values for sex steroids and SHBG when investigating their impact on health outcomes to prevent controversial results and allow for their appropriate clinical application.

Maternal lipid profile in pregnancy and embryonic size: a population-based prospective cohort study.

BACKGROUND: Lipids are crucial for fetal growth and development. Maternal lipid concentrations are associated with fetal growth in the second and third trimester of pregnancy and with birth outcomes. However, it is unknown if this association starts early in pregnancy or arises later during fetal development. The aim of this study was to investigate the association between the maternal lipid profile in early pregnancy and embryonic size. METHODS: We included 1474 women from the Generation R Study, a population based prospective birth cohort. Both embryonic size and the maternal lipid profile were measured between 10 weeks + 1 day and 13 weeks + 6 days gestational age. The maternal lipid profile was defined as total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), remnant cholesterol, non-high-density (non-HDL-c) lipoprotein cholesterol concentrations and the triglycerides/high-density lipoprotein (TG/HDL-c) ratio. Additionally, maternal glucose concentrations were assessed. Embryonic size was assessed using crown-rump length (CRL) measurements. Associations were studied with linear regression models, adjusted for confounding factors: maternal age, pre-pregnancy body mass index (BMI), parity, educational level, ethnicity, smoking and folic acid supplement use. RESULTS: Triglycerides and remnant cholesterol concentrations are positively associated with embryonic size (fully adjusted models, 0.17 SDS CRL: 95% CI 0.03; 0.30, and 0.17 SDS: 95% CI 0.04; 0.31 per 1 MoM increase, respectively). These associations were not present in women with normal weight (triglycerides and remnant cholesterol: fully adjusted model, 0.44 SDS: 95% CI 0.15; 0.72). Associations between maternal lipid concentrations and embryonic size were not attenuated after adjustment for glucose concentrations. Total cholesterol, HDL-c, LDL-c, non-HDL-c concentrations and the TG/HDL-c ratio were not associated with embryonic size. CONCLUSIONS: Higher triglycerides and remnant cholesterol concentrations in early pregnancy are associated with increased embryonic size, most notably in overweight women. TRIAL REGISTRATION: The study protocol has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre (Erasmus MC), Rotterdam (MEC-2007-413). Written informed consent was obtained from all participants.

Maternal lipid levels in early pregnancy as a predictor of childhood lipid levels: a prospective cohort study.

BACKGROUND: Maternal lipid levels in early pregnancy are associated with maternal health and foetal growth. It is however unclear if maternal lipids in early pregnancy can be used to predict childhood lipid levels. The aim of this study is to assess the association between maternal and offspring childhood lipid levels, and to investigate the influence of maternal BMI and diet on these associations. METHODS: This study included 2692 women participating in the Generation R study, an ongoing population-based prospective cohort study from early life onwards. Women with an expected delivery date between 2002 and 2006 living in Rotterdam, the Netherlands were included. Total cholesterol, triglycerides and high-density lipoprotein cholesterol (HDL-c) were measured in early pregnancy (median 13.2 weeks [90% range 10.6; 17.1]). Low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated. Corresponding lipid measurements were determined in 2692 children at the age of 6 (median 6.0 years [90% range 5.7; 7.5]) and 1673 children 10 years (median 9.7 years [90% range 9.5; 10.3]). Multivariate linear regression analysis was used to examine the association between maternal lipid levels in early pregnancy and the corresponding childhood lipid measurements at the ages of 6 and 10 years while adjusting for confounders. RESULTS: Maternal lipid levels in early pregnancy are positively associated with corresponding childhood lipid levels 6 and 10 years after pregnancy, independent of maternal body mass index and diet. CONCLUSIONS: Maternal lipid levels in early pregnancy may provide an insight to the lipid profile of children years later. Gestational lipid levels may therefore be used as an early predictor of children's long-term health. Monitoring of these gestational lipid levels may give a window-of-opportunity to start early interventions to decrease offspring's lipid levels and possibly diminish their cardiovascular risk later in life. Future studies are warranted to investigate the genetic contribution on maternal lipid levels in pregnancy and lipid levels of their offspring years later.

Novel associations between parental and newborn cord blood metabolic profiles in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: More than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring's cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal and paternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile. METHODS: This study is based on 710 mother-father-newborn trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in this study consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure was used to correct for multiple testing. RESULTS: Among mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoprotein cholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine, creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated (0.001 ≤ q ≤ 0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine, tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoprotein were significantly positively associated (0.02 ≤ q ≤ 0.08). Among fathers with hypercholesterolemia, paternal and newborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q = 0.04). Among fathers without hypercholesterolemia, no significant associations were found between paternal and newborn metabolites. Sex differences were found for many cord blood lipids. CONCLUSIONS: Maternal and paternal metabolites and newborn sex were associated with several cord blood metabolites. This may potentially affect the offspring's long-term cardiovascular disease risk.

Placental Growth Factor as an Indicator of Maternal Cardiovascular Risk After Pregnancy.

BACKGROUND: Angiogenic placental growth factor (PlGF) concentrations rise during pregnancy, peaking at the end of midpregnancy. Low PlGF concentrations during pregnancy are associated with pregnancy complications with recognized later-life cardiovascular risk. We hypothesized that low PlGF concentrations, especially in midpregnancy, identify not only a subset of women at risk for pregnancy complications but also women with greater cardiovascular risk factor burden after pregnancy regardless of pregnancy outcome. METHODS: In a population-based prospective cohort study of 5475 women, we computed gestational age-adjusted multiples of the medians of early pregnancy and midpregnancy PlGF concentrations. Information on pregnancy complications (preeclampsia, small for gestational age, and spontaneous preterm birth) was obtained from hospital registries. Six years after pregnancy, we measured maternal systolic and diastolic blood pressures, cardiac structure (aortic root diameter, left atrial diameter, left ventricular mass, and fractional shortening), carotid-femoral pulse wave velocity, and central retinal arteriolar and venular calibers. Blood pressure was also measured 9 years after pregnancy. RESULTS: Women were on average 29.8 (SD, 5.2) years of age in pregnancy, were mostly European (55.2%), and 14.8% developed a pregnancy complication. Quartile analysis showed that especially women with midpregnancy PlGF in the lowest quartile (the low-PlGF subset) had a larger aortic root diameter (0.40 mm [95% CI, 0.08-0.73]), left atrial diameter (0.34 mm [95% CI, -0.09 to 0.78]), left ventricular mass (4.6 g [95% CI, 1.1-8.1]), and systolic blood pressure (2.3 mm Hg [95% CI, 0.93-3.6]) 6 years after pregnancy than women with the highest PlGF. Linear regression analysis showed that higher midpregnancy PlGF concentrations were associated with a smaller aortic root diameter (-0.24 mm [95% CI, -0.39 to -0.10]), smaller left atrial diameter (-0.75 mm [95% CI, -0.95 to -0.56]), lower left ventricular mass (-3.9 g [95% CI, -5.5 to -2.3]), and lower systolic blood pressure (-1.1 mm Hg [95% CI, -1.7 to -0.46]). These differences persisted after the exclusion of women with complicated pregnancies. CONCLUSIONS: Women with low PlGF in midpregnancy have a greater aortic root diameter, left atrial diameter, and left ventricular mass and higher systolic blood pressure 6 and 9 years after pregnancy compared to women with higher PlGF, including women with uncomplicated pregnancies. The pathophysiological implications of lower PlGF concentrations in midpregnancy might provide insight into the identification of pathways contributing to greater cardiovascular risk factor burden.

Maternal lipid profile in early pregnancy is associated with foetal growth and the risk of a child born large-for-gestational age: a population-based prospective cohort study : Maternal lipid profile in early pregnancy and foetal growth.

BACKGROUND: Lipids such as cholesterol and triglycerides play an important role in both maternal and foetal energy metabolism. Little is known about maternal lipid levels in pregnancy and their effect on foetal growth. The aim of this study was to assess maternal lipid levels, foetal growth and the risk of small-for-gestational age (SGA) and large-for-gestational age (LGA). METHODS: We included 5702 women from the Generation R Study, a prospective population-based cohort. Maternal lipid levels (total cholesterol, triglycerides and high-density lipoprotein cholesterol [HDL-c]) were measured in early pregnancy (median 13.4 weeks, 90% range [10.5 to 17.2]). Low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated. Foetal growth was measured repeatedly by ultrasound. Information on birth anthropometrics was retrieved from medical records. A birth weight below the 10th percentile was defined as SGA and above the 90th percentile as LGA. RESULTS: Maternal triglyceride and remnant cholesterol levels were associated with increased foetal head circumference and abdominal circumference growth rates. Triglycerides and remnant cholesterol were positively associated with the risk of LGA (odds ratio [OR] 1.11, 95% confidence interval [CI] [1.01 to 1.22] and OR 1.11, 95% CI [1.01 to 1.23], respectively). These associations were independent of maternal pre-pregnancy body mass index, but not maternal glucose levels. We observed no association between maternal lipids in early pregnancy and SGA. CONCLUSIONS: Our study suggests a novel association of early pregnancy triglyceride and remnant cholesterol levels with foetal growth, patterns of foetal growth and the risk of LGA. Future studies are warranted to explore clinical implication possibilities.

Gestational lipid profile as an early marker of metabolic syndrome in later life: a population-based prospective cohort study.

BACKGROUND: In pregnancy lipid levels increase with gestation resembling an atherogenic lipid profile. Currently it is unclear whether gestational lipid levels are associated with an adverse cardiovascular risk profile later in life. The aim of this study is to assess the association between gestational lipid levels and lipid levels and prevalence of the metabolic syndrome (MS) six years after pregnancy. METHODS: In plasma of 3510 women from the Generation R Study; a prospective population-based cohort, we measured lipid levels (total cholesterol, triglycerides and high-density lipoprotein cholesterol [HDL-c]), and low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated in early pregnancy (median 13.2 weeks, 90% range [10.5 to 17.1]) and six years after pregnancy (median 6.5 years, 90% range [6.2 to 7.8]). MS was assessed six years after pregnancy according to the NCEP/ATP3 criteria. We also examined the influence of pregnancy complications on these associations. RESULTS: Gestational lipid levels were positively associated with corresponding lipid levels six years after pregnancy, independent of pregnancy complications. Six years after pregnancy the prevalence of MS was 10.0%; the prevalence was higher for women with a previous placental syndrome (13.5%). Gestational triglycerides and remnant cholesterol in the highest quartile and HDL-c in the lowest quartile were associated with the highest risk for future MS, independent of smoking and body mass index. CONCLUSIONS: Gestational lipid levels provide an insight in the future cardiovascular risk profile of women in later life. Monitoring and lifestyle intervention could be indicated in women with an unfavorable gestational lipid profile to optimize timely cardiovascular risk prevention.

Is maternal lipid profile in early pregnancy associated with pregnancy complications and blood pressure in pregnancy and long term postpartum?

BACKGROUND: An atherogenic lipid profile is a risk factor for the initiation and progression of atherosclerosis. This ultimately leads to cardiovascular disease. Women with a history of hypertensive disorders of pregnancy are at increased risk of sustained hypertension and cardiovascular disease later in life. Currently it is unclear whether dyslipidemia during pregnancy contributes to these risks. OBJECTIVE: The objective of the study was to determine the associations between early pregnancy maternal lipid profile, hypertensive disorders of pregnancy, and blood pressure during and years after pregnancy. STUDY DESIGN: We included 5690 women from the Generation R Study, an ongoing population-based prospective birth cohort. Two hundred eighteen women (3.8%) developed gestational hypertension and 139 (2.4%) preeclampsia. A maternal lipid profile consisting of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, remnant cholesterol, and non-high-density lipoprotein cholesterol was determined in early pregnancy (median, 13.4 weeks of gestation). Systolic and diastolic blood pressures were measured in early, mid-, and late pregnancy and 6 and 9 years after pregnancy. RESULTS: Triglycerides and remnant cholesterol in early pregnancy were positively associated with preeclampsia. Maternal lipid levels in early pregnancy were not associated with gestational hypertension. Total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and especially triglycerides and remnant cholesterol were positively associated with blood pressure in pregnancy and 6 and 9 years after pregnancy. Triglycerides and remnant cholesterol are positively associated with sustained hypertension 6 and 9 years after pregnancy. CONCLUSION: An atherogenic lipid profile in early pregnancy reflecting impaired triglyceride-rich lipoprotein metabolism is independently associated with preeclampsia and blood pressure throughout pregnancy but also with sustained hypertension long term postpartum. Lipid levels in early pregnancy may help to identify women at risk for future hypertension and perhaps also women at risk for future cardiovascular disease.

Biosimilars of low molecular weight heparins: Relevant background information for your drug formulary.

Biosimilars of low molecular weight heparins (LMWHs) are more alike the originator than different branded LMWHs. The latter differ largely in molecular weight, anti-FXa/anti-FIIa ratio and antithrombin binding. The Food and Drug Administration and European Medicines Agency guidelines are sufficient for the clinical use of high quality LMWHs. However, the Food and Drug Administration guideline lacks the results of a phase I clinical trial in the approval process. Most information about biosimilars is available for enoxaparin given that many biosimilars of enoxaparin have received market access. The guidelines of many International Thrombosis Societies for LMWH biosimilars are too stringent, not updated and impractical for formulary uptake discussions. This review gives background information on critical factors for the formulary uptake process of LMWHs with special attention for the use of the System of Objectified Judgment Analysis/Infomatrix model.

Hypertensive disorders of pregnancy and subsequent maternal cardiovascular health.

To examine associations between hypertensive pregnancy disorders and maternal cardiovascular disease (CVD) in later life. We examined the associations between blood pressure (BP) in pregnancy, gestational hypertension (GH) and preeclampsia (PE) with cardiovascular measurements 6 years after index pregnancy among 4912 women participating in the Generation R Study, the Netherlands. BP, left ventricular mass (LV mass), aortic root diameter (AOD), left atrial diameter, fractional shortening, and carotid-femoral pulse wave velocity (PWV). Early pregnancy systolic and diastolic BP were associated with more adverse maternal cardiovascular measurements and a higher incidence of chronic hypertension 6 years after pregnancy. GH was associated with a higher BP, a higher PWV, a larger AOD and an increased LV mass 6 years after index pregnancy. Compared to previous normotensive pregnancies these women had a sixfold increased risk to develop chronic hypertension after pregnancy (OR 6.6, 95% CI 4.6-9.5). Compared to women with a normotensive pregnancy, women with PE had a higher BP and a higher risk of chronic hypertension (OR 4.5, 95% CI 2.6-7.8) at follow-up. After adjustment for BMI at follow-up in all the analyses on GH, PE and cardiovascular measurements, effect estimates attenuated up to 65%, but remained significant. Both GH and PE are associated with markers of adverse maternal cardiovascular health after pregnancy with an increased risk of chronic hypertension. Women with GH and PE may be offered long-term cardiovascular follow-up incorporated in CVD risk management guidelines.

Effect of diet-induced weight loss on lipoprotein(a) levels in obese individuals with and without type 2 diabetes.

AIMS/HYPOTHESIS: Elevated levels of lipoprotein(a) [Lp(a)] are an independent risk factor for cardiovascular disease (CVD), particularly in individuals with type 2 diabetes. Although weight loss improves conventional risk factors for CVD in type 2 diabetes, the effects on Lp(a) are unknown and may influence the long-term outcome of CVD after diet-induced weight loss. The aim of this clinical study was to determine the effect of diet-induced weight loss on Lp(a) levels in obese individuals with type 2 diabetes. METHODS: Plasma Lp(a) levels were determined by immunoturbidimetry in plasma obtained before and after 3-4 months of an energy-restricted diet in four independent study cohorts. The primary cohort consisted of 131 predominantly obese patients with type 2 diabetes (cohort 1), all participants of the Prevention Of Weight Regain in diabetes type 2 (POWER) trial. The secondary cohorts consisted of 30 obese patients with type 2 diabetes (cohort 2), 37 obese individuals without type 2 diabetes (cohort 3) and 26 obese individuals without type 2 diabetes who underwent bariatric surgery (cohort 4). RESULTS: In the primary cohort, the energy-restricted diet resulted in a weight loss of 9.9% (95% CI 8.9, 10.8) and improved conventional CVD risk factors such as LDL-cholesterol levels. Lp(a) levels increased by 14.8 nmol/l (95% CI 10.2, 20.6). In univariate analysis, the change in Lp(a) correlated with baseline Lp(a) levels (r = 0.38, p < 0.001) and change in LDL-cholesterol (r = 0.19, p = 0.033). In cohorts 2 and 3, the weight loss of 8.5% (95% CI 6.5, 10.6) and 6.5% (95% CI 5.7, 7.2) was accompanied by a median increase in Lp(a) of 13.5 nmol/l (95% CI 2.3, 30.0) and 11.9 nmol/l (95% CI 5.7, 19.0), respectively (all p < 0.05). When cohorts 1-3 were combined, the diet-induced increase in Lp(a) correlated with weight loss (r = 0.178, p = 0.012). In cohort 4, no significant change in Lp(a) was found (-7.0 nmol/l; 95% CI -18.8, 5.3) despite considerable weight loss (14.0%; 95% CI 12.2, 15.7). CONCLUSIONS/INTERPRETATION: Diet-induced weight loss was accompanied by an increase in Lp(a) levels in obese individuals with and without type 2 diabetes while conventional CVD risk factors for CVD improved. This increase in Lp(a) levels may potentially antagonise the beneficial cardiometabolic effects of diet-induced weight reduction.

Gestational hypertensive disorders and retinal microvasculature: the Generation R Study.

BACKGROUND: Changes in the microvasculature associated with pre-eclampsia and gestational hypertension have been proposed as a potential pathway in the development of cardiovascular disease. We examined whether gestational hypertensive disorders, such as pre-eclampsia and gestational hypertension, are related to the maternal retinal microvasculature status after pregnancy. METHODS: This study is part of an ongoing population-based prospective cohort study. During pregnancy and 6.2 years after the index pregnancy (90% range 5.7-7.4 years), we examined 3391 women with available information on pre-eclampsia, gestational hypertension, and retinal vascular calibers. Retinal arteriolar and venular calibers were measured in the left eye from digitized retinal photographs. RESULTS: Women with pre-eclampsia had smaller retinal arteriolar calibers 6 years after pregnancy than women with a normotensive pregnancy (adjusted difference: -0.40 standard deviation score [SDS]; 95% confidence interval [CI]: -0.62, -0.19). For women with previous gestational hypertension, similar trends were observed (-0.20 SDS; 95% CI: -0.34, -0.05). With respect to retinal venular calibers, we did not observe consistent trends for women with previous pre-eclampsia. However, in women with previous gestational hypertension, we observed larger venular calibers (0.22 SDS; 95% CI: 0.07-0.36) than in women with a previous normotensive pregnancy. The association of gestational hypertensive disorders with retinal vessel calibers was mediated through mean arterial pressure at the time of retinal imaging. CONCLUSIONS: Compared to women with a previous normotensive pregnancy, women with pre-eclampsia and gestational hypertension show an altered status of the microvasculature 6 years after the index pregnancy. This is reflected by smaller retinal arteriolar calibers and wider retinal venular calibers. These microvascular changes may possibly contribute to the development of cardiovascular disease in later life.