ALBERT

Description: Venous thromboembolism (VTE)during pregnancy is still an important cause of maternal morbidity and mortality in the Western world. The risk VTE in pregnant women is five times higher than in non-pregnant women of the same age. This risk is increased by thrombophilic defects. In a family cohort study we assessed the risk of VTE during pregnancy/puerperium and the contribution of concomitant thrombophilic defects in women with hereditary antithrombin, protein C or protein S deficiencies. Women were recruited from a previous large family cohort study, which was designed to estimate the risk of VTE in first degree relatives from probands with documented VTE and a deficiency of antithrombin, protein C or protein S. Probands were excluded from analysis. Blood samples of female relatives were tested on the index deficiencies and prothrombin G20210A, factor V Leiden, hyperhomocysteinemia and increased levels of VIII:C, IX:C and XI:C. Observation time was defined as the fertile period (from age 15–45 years), or until the first VTE, or until end of study period. The cohort contained 222 female relatives, of whom 101 women were deficient and 121 non-deficient. The absolute risk of venous thromboembolism in deficient women was 1.76 per 100 person-years versus 0.19 per 100 person-years in non-deficient women (Relative Risk (RR) 9.2; 95% CI 3.8–26.7). Concomitance of none, one and more than one thrombophilic defect increased the risk in deficient (1.55, 2.14 and 2.92 per 100 person-years, respectively) and non-deficient women (0.16, 0.09 and 0.54 per 100 person -years, respectively). Annual incidences (AI) were lower in ever pregnant than never pregnant deficient women, 1.37 per 100 person-years versus 2.96 per 100 person-years (RR 0.5; 95% CI 0.2–0.99)(Table). These were 0.09 per 100 person-years versus 0.70 per 100 person-years in non-deficient women (RR 0.1; 95% CI 0.02–0.9). In ever pregnant deficient women 71% of VTE episodes were pregnancy related. A majority (75%) of never pregnant deficient women revealed VTE associated with oral contraceptives. Women with hereditary antithrombin, protein C or protein S deficiencies are at high risk of VTE. Concomitance of other thrombophilic defects increased this risk. In fertile women most episodes of VTE are associated with either pregnancy or oral contraceptives. Deficient Non-deficient Ever pregnant (n=54) Never Pregnant (n=47) Ever pregnant (n=79) Never pregnant (n=42) Women with VTE, n 17 12 2 3 Observation period, yr 1241 405 2169 430 AI, % (95% CI) 1.37 (0.80–2.19) 2.96 (1.53–5.18) 0.09 (0.01–0.33) 0.70 (0.14–2.04) RR (95% CI) 0.5 (0.2–0.99) P=0.05 0.1 (0.02–0.9) P=0.04 Pregnancy related VTE, n (%) 12 (71) 0 1 (50) 0 Oral contraceptive related VTE, n (%) 2 (12) 9 (75) 0 3 (100)

Description: We reported earlier that an anti-inflammatory small peptide receptor-formyl peptide receptor-2 (FPR2) was significantly decreased in placentas from third trimester pregnancies complicated with fetal growth restriction (FGR), compared to placentas from uncomplicated control pregnancies, suggesting FPR2 may play a role in the development of FGR. The aim of this study is to investigate whether the actions of FPR2 alters placental growth process in humans. Accordingly, using small-for-gestation age (SGA) as a proxy for FGR, we hypothesize that FPR2 expression is decreased in first-trimester placentas of women who later manifest FGR, and contributes to aberrant trophoblast function and the development of FGR. Chorionic villus sampling (CVS) tissues were collected at 10–12 weeks gestation in 70 patients with singleton fetuses; surplus tissue was used. Real-time PCR and immunoassays were performed to quantitate FPR2 gene and protein expression. Silencing of FPR2 was performed in two independent, trophoblast-derived cell lines, HTR-8/SVneo and JEG-3 to investigate the functional consequences of FPR2 gene downregulation. FPR2 mRNA relative to 18S rRNA was significantly decreased in placentae from SGA-pregnancies (n = 28) compared with controls (n = 52) (p 〈 0.0001). Placental FPR2 protein was significantly decreased in SGA compared with control (n = 10 in each group, p 〈 0.05). Proliferative, migratory and invasive potential of the human placental-derived cell lines, HTR-8/SVneo and JEG-3 were significantly reduced in siFPR2 treated cells compared with siCONT control groups. Down-stream signaling molecules, STAT5B and SOCS3 were identified as target genes of FPR2 action in the trophoblast-derived cell lines and in SGA and control chorionic villous tissues. FPR2 is a novel regulator of key molecular pathways and functions in placental development, and its decreased expression in women destined to develop FGR reinforces a placental origin of SGA/FGR, and that it contributes to causing the development of SGA/FGR.

Description: The preconception period has been recognized as one of the earliest sensitive windows for human development. Maternal dietary intake during this period may influence the oocyte quality, as well as placenta and early embryonic development during the first trimester of pregnancy. Previous studies have found associations between macronutrient intake during preconception and pregnancy outcomes. However, as food products consist of multiple macro- and micronutrients, it is difficult to relate this to dietary intake behavior. Therefore, the aim of this study was to investigate the association between intake of specific food groups during the preconception period with birth weight, using data from the Perined-Lifelines linked birth cohort. The Perined-Lifelines birth cohort consists of women who delivered a live-born infant at term after being enrolled in a large population-based cohort study (The Lifelines Cohort). Information on birth outcome was obtained by linkage to the Dutch perinatal registry (Perined). In total, we included 1698 women with data available on birth weight of the offspring and reliable detailed information on dietary intake using a semi-quantitative food frequency questionnaire obtained before pregnancy. Based on the 2015 Dutch Dietary Guidelines and recent literature 22 food groups were formulated. Birth weight was converted into gestational age-adjusted z-scores. Multivariable linear regression was performed, adjusted for intake of other food groups and covariates (maternal BMI, maternal age, smoking, alcohol, education level, urbanization level, parity, sex of newborn, ethnicity). Linear regression analysis, adjusted for covariates and intake of energy (in kcal) (adjusted z score [95% CI], P) showed that intake of food groups “artificially sweetened products” and “vegetables” was associated with increased birth weight (resp. (β = 0.001 [95% CI 0.000 to 0.001, p = 0.002]), (β = 0.002 [95% CI 0.000 to 0.003, p = 0.03])). Intake of food group “eggs” was associated with decreased birth weight (β = −0.093 [95% CI −0.174 to −0.013, p = 0.02]). Intake in food groups was expressed in 10 g per 1000 kcal to be able to draw conclusions on clinical relevance given the bigger portion size of the food groups. In particular, preconception intake of “artificially sweetened products” was shown to be associated with increased birth weight. Artificial sweeteners were introduced into our diets with the intention to reduce caloric intake and normalize blood glucose levels, without compromising on the preference for sweet food products. Our findings highlight the need to better understand how artificial sweeteners may affect the metabolism of the mother and her offspring already from preconception onwards.