J.E. Roeters van Lennep

Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: Is it effective?

Summary.  Background: The optimal approach for venous thrombosis (VTE) prophylaxis during pregnancy and postpartum in women with an increased risk of VTE is not established. Objectives: To evaluate the effectiveness, represented as the incidence of pregnancy‐related VTE, and safety, represented as incidence of postpartum hemorrhage (PPH), of a protocol recommending prophylaxis with low‐dose low‐molecular‐weight heparin (LMWH) in women at intermediate to high risk of VTE. Patients/methods: In this retrospective cohort study, we analyzed 34 women (44 pregnancies) with intermediate risk of VTE who received low‐dose LMWH for 6 weeks postpartum and 57 women (82 pregnancies) with high risk of VTE who received low‐dose LMWH during pregnancy and for 6 weeks postpartum. Pregnancy‐related VTE was defined as VTE during pregnancy or ≤ 3 months postpartum. PPH was defined as blood loss > 500 mL and severe PPH as blood loss > 1000 mL. Results: The incidence of pregnancy‐related VTE was 5.5% (95% CI, 2.4–12.3) despite prophylaxis with low‐dose LMWH. All events occurred in women at high risk, with a postpartum incidence of 7.0% (95% CI, 2.9–16.7) and antepartum incidence of 1.8% (95% CI, 0.4–9.2). The risk of PPH was 21.6% (95% CI, 14.3–31.3) and severe PPH 9.1% (95% CI, 4.7–16.9), which was not different in women who started LMWH postpartum and those who used LMWH during pregnancy. Conclusions: Although prophylaxis with low‐dose LMWH during pregnancy and postpartum proved to be safe, the risk of pregnancy‐related VTE is considerable in women with a high risk of VTE. VTE prophylaxis with low‐dose LMWH may not be sufficiently effective in these women.

Lipoprotein(a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia

Lipoprotein(a) [Lp(a)] is an independent risk factor for aortic valve stenosis and aortic valve calcification (AVC) in the general population. In this study, we determined the association between AVC and both plasma Lp(a) levels and apolipoprotein(a) [apo(a)] kringle IV repeat polymorphisms in asymptomatic statin‐treated patients with heterozygous familial hypercholesterolaemia (FH).

Cascade screening of familial hypercholesterolemia must go on

PURPOSE This study assesses the success of the recently terminated Dutch nationwide cascade screening by examining whether children with familial hypercholesterolemia (FH) were identified through family screening or due to cardiovascular (CVD) events in the FH parent. METHODS We collected clinical information of all children (0-18 years) with FH with a pathogenic variant at our outpatient lipid clinic between 1992 and 2014 and their FH parents and FH grandparents. RESULTS We analysed 292 FH children from 205 parents with FH. A history of premature CVD was present in 20% of the parents (29% of the fathers, 9% of the mothers) and 49% of the FH grandparents. CONCLUSION The fact that CVD is still a presenting event of FH in especially fathers shows that nationwide screening might have been terminated too early. Therefore we recommend to proceed the cascade screening.

Excess mortality in mothers of patients with polycystic ovary syndrome

STUDY QUESTION Do diabetic parents of patients with polycystic ovary syndrome (PCOS) encounter excess mortality compared with the mortality of men and women with type 2 diabetes, recruited without selection for PCOS? SUMMARY ANSWER Type 2 diabetes among mothers of PCOS patients results in excess mortality compared with women with diabetes from the general population. WHAT IS KNOWN ALREADY Insulin resistance is a prominent feature of PCOS. Because of the heritable nature of PCOS, parents of these patients are also prone to develop type 2 diabetes mellitus, which might influence their life expectancy. STUDY DESIGN, SIZE, DURATION This reverse parent-offspring study included 946 mothers and 902 fathers of patients with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS The medical history of the parents was primarily obtained during the initial screening of each patient and updated via questionnaires. Mortality data of these parents were compared with the mortality rates of the general Dutch population and with mortality rates of a control population consisting of 1353 men and women diagnosed with type 2 diabetes mellitus. The standardized mortality ratio (SMR) was calculated as the ratio of the observed mortality of the parents to the expected mortality in the general Dutch population. The mortality of parents with type 2 diabetes mellitus relative to controls with diabetes but not related to anyone with PCOS was standardized for age, gender and calendar period using Poisson regression. MAIN RESULTS AND ROLE OF CHANCE In total, 302 parents were deceased in 62 693 person-years. Mothers above age 60 had a significant excess mortality of 1.50 (95% CI 1.15-1.92) compared with the general Dutch population. Moreover, mothers with diabetes had two-times higher mortality risk compared with control women with diabetes (RR 2.0, 95% CI 1.19-3.41). No excess mortality among fathers of PCOS patients was observed. LIMITATIONS, REASON FOR CAUTION Although recall bias for family history was previously demonstrated to be minimal for long-term chronic diseases, the prevalence of diabetes in the parents was based on their daughters self-report and was not clinically confirmed. Also, no other additional clinical data regarding the parent population were available. Prospective long-term follow-up studies should be conducted to confirm this excess mortality. WIDER IMPLICATIONS OF THE FINDINGS Our findings justify screening for type 2 diabetes mellitus among the mothers with a daughter suffering from PCOS to ensure that timely preventive and therapeutic measures according to the appropriate guidelines can be taken. STUDY FUNDING/COMPETING INTERESTS No particular funding was received for this study. Y.V.L., M.E.R.-S., N.K., J.R.v.L., M.v.d.B., H.J.G.B. and E.J.G.S. do not have any conflict of interest. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono, and Wyeth. These companies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Dyslipidemia testing: Why, for whom and when

Dyslipidemia is a major risk factor for cardiovascular disease. This review addresses why, who and when to test for dyslipidemia. The essence why to test lipids is that those individuals recognized to potentially benefit from primary cardiovascular risk prevention, have a complete cardiovascular risk assessment. Who and when to test lipids differs among the major European, English and American guidelines regarding the recommended age and approach. It is important to note that the threshold and the frequency in whom to perform risk assessment is not established. Most important in decisions concerning lipid testing is communication and to involve individual circumstances.

Soluble fms‐like tyrosine kinase‐1 and placental growth factor kinetics during and after pregnancy in women with suspected or confirmed pre‐eclampsia

To assess the evolution of the soluble fms‐like tyrosine kinase‐1 (sFlt‐1) to placental growth factor (PlGF) ratio in women with suspected or confirmed pre‐eclampsia (PE), and to investigate the changes in sFlt‐1 and PlGF levels in pre‐eclamptic women after delivery.Objectives To assess the evolution of the sFlt-1/PlGF ratio in women with suspected or with confirmed preeclampsia and to investigate the changes in sFlt-1 and PlGF levels in preeclamptic women after delivery. Methods In this exploratory tertiary referral university centre study, using the Roche Diagnostics Elecsys assay, sFlt-1 and PlGF were determined in two groups of patients. In the first group of 46 patients with suspected or confirmed preeclampsia, sFlt-1 and PlGF were measured at least twice during their pregnancy. Women had singleton pregnancies and a median pregnancy duration of 26 weeks (range 18 – 40 weeks). In the second group, sFlt-1 and PlGF of 26 preeclamptic patients were determined before and after delivery. The median gestational age at inclusion was 29 weeks (16 – 37) and the median days between antepartum measurement and delivery was 2 days (1 – 7). Results In the first group, 90% of patients with a sFlt-1/PlGF ratio ≤38 at baseline (n = 30), ruling out PE, the sFlt-1/PlGF ratio remained stable for up to 100 days. In 16 patients with a sFlt-1/PlGF ratio >38 and in 10% of those with a sFlt-1/PlGF ratio <38 at baseline the ratio increased further. In the second group, after delivery, sFlt-1 dropped to <1% of its pre-delivery values with a half-life of 1.4 ± 0.3 days, while PlGF dropped to ≈ 30% of its pre-delivery values with a half-life of 3.7 ± 4.3 days. Conclusions Based on this small cohort, up to 10% of women admitted with suspected or confirmed PE presenting with a sFlt-1/PlGF ratio ≤38 display a rise of this sFlt-1/PlGF ratio in subsequent weeks, implying that repeated determination of the sFlt-1/PlGF ratio is required to reject this condition definitively. Furthermore, the rapid and pronounced decline of sFlt-1 values after delivery in patients with PE/HELLP suggests that sFlt-1, in contrast with PlGF, is almost entirely placenta-derived.

The periconception maternal cardiovascular risk profile influences human embryonic growth trajectories in IVF/ICSI pregnancies

STUDY QUESTION Is the maternal cardiovascular (CV) risk profile associated with human embryonic growth trajectories and does the mode of conception affect this association? SUMMARY ANSWER This small study suggests that the maternal CV risk profile is inversely associated with first trimester embryonic growth trajectories in in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) pregnancies, but not in spontaneously conceived pregnancies. WHAT IS KNOWN ALREADY Maternal high-blood pressure and smoking affect placental function, accompanied by increased risk of fetal growth restriction and low-birthweight. Mothers who experience pregnancies complicated by fetal growth restriction are at increased risk of CV disease in later life. STUDY DESIGN, SIZE, DURATION In a prospective periconception birth cohort conducted in a tertiary hospital, 111 singleton ongoing pregnancies with reliable pregnancy dating, no pre-existing maternal disease and no malformed live borns were investigated. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Spontaneously conceived pregnancies with a reliable first day of the last menstrual period and a regular menstrual cycle of 25-31 days only (n = 66) and IVF/ICSI pregnancies (n = 45) were included. Women underwent weekly three-dimensional ultrasound scans (3D US) from 6- to 13-week gestational age. To estimate embryonic growth, serial crown-rump length (CRL) measurements were performed using the V-Scope software in a BARCO I-Space. Maternal characteristics and CV risk factors were collected by self-administered questionnaires. The CV risk profile was created based on a score of risk factors, including maternal age, body-mass index, CV disease in the family, diet and smoking. Quartiles of the CV risk score were calculated. Associations between the CV risk score and embryonic growth were assessed using square root transformed CRL in multivariable linear mixed model analyses. MAIN RESULTS AND THE ROLE OF CHANCE From the 111 included pregnancies, 696 3D US data sets were obtained of which 637 (91.5%) CRLs could be measured. In the total group, The CV risk score was inversely, but not significantly associated with embryonic growth (-0.03√mm; P = 0.291). Stratified by mode of conception, the CV risk score was inversely and significantly associated with embryonic growth (β = -0.04√mm; P = 0.025, adjusted for possible confounders) in the IVF/ICSI group. Compared with the first quartile, embryos in the upper quartile were 10.4% smaller at 6(+0) weeks (4.4 versus 4.9 mm) and 3.1% smaller at 12(+0) weeks (56.5 versus 58.4 mm) of gestation. Although the CV risk score was slightly, but significantly, higher in women conceiving spontaneously compared with those undergoing IVF/ICSI treatment [CV risk score = 2.06 (SD: 1.23) and 1.60 (SD: 1.15), respectively], no association was established with embryonic growth in that particular group. LIMITATIONS, REASONS FOR CAUTION Participants included in the present cohort are women with a singleton ongoing pregnancy without any pre-existing disease and selected from a tertiary hospital. Hence, they represent a selected group of women. Larger and population-based periconception birth cohort studies are recommended to demonstrate external validity. WIDER IMPLICATIONS OF THE FINDINGS Differences in embryonic growth between pregnancies conceived spontaneously and after IVF/ICSI treatment in relation with CV risk factors substantiate the importance of more investigation into differences in sensitivity of endometrial, endothelial, placental and embryonic tissues. STUDY FUNDING/COMPETING INTERESTS Funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands. The authors declare no conflict of interest.

Low‐molecular‐weight‐heparin and pregnancy, when the dose does it: a nephrologist’s opinion: reply to a rebuttal

See also Roeters van Lennep JE, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S. Prophylaxis with low‐dose low‐molecular‐weight‐heparin during pregnancy and postpartum: is it effective? J Thromb Haemost 2011; 9: 473–80; Stratta P, Canavese C, Cena T, Quaglia M, Pergolini P, Bellomo G, Magnani C. Low‐molecular‐weight‐heparin and pregnancy, when the dose does it: a nephrologist’s opinion: a rebuttal. This issue, pp 2127–9.

[PP.23.15] THE EVOLUTION OF SFLT-1/PLGF RATIO DURING PREGNANCY IN WOMEN WITH (SUSPECTED) PREECLAMPSIA

Objective: To assess the evolution of the sFlt-1/PlGF ratio in women with (suspected) preeclampsia on clinical grounds. Design and method: sFlt-1 and PlGF serum concentration were determined (Elecsys assay, Roche Diagnostics) at =/> 2 time points in women with (suspected) preeclampsia based on the presence of =/> 1 of the following symptoms: new onset or aggravation of hypertension or proteinuria; renal insufficiency (serum creatinine >100 &mgr;mol/l); neurological complications (severe headache, hyperreflexia, persistent visual scotoma, blindness, stroke, seizures); severe oedema or HELLP symptoms (right upper quadrant/epigastric abdominal pain; elevated transaminases; thrombocytopenia; haemolysis). Results: We included 46 women (singleton pregnancies), aged 18–47 years with median pregnancy duration of 35 weeks (range 20–41 weeks). In 90% of patients with a sFlt-1/PlGF ratio </=38 (median 8, range 2, 37) at baseline (n=30), ruling out preeclampsia, the ratio remained stable for up to 100 days. In 16 patients with a ratio >38 (median 98, range 42, 991) at baseline the ratio increased further over time, roughly doubling every week. Conclusions: In a small proportion of women admitted for evaluation of preeclampsia, who presented with a sFlt-1/PlGF ratio </=38 at initial assessment, this ratio rose in subsequent weeks, implying that repeated determination of the ratio is required to reject this condition definitively.