Obstetric and perinatal risks after the use of donor sperm: A systematic review and meta-analysis.

Donor sperm is widely used in infertility treatments. The purpose of the study was to investigate, whether use of donor sperm in intrauterine insemination (IUI) or in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments affect maternal and perinatal risks compared with spontaneously conceived pregnancies or use of partner sperm in IUI, IVF or ICSI. We provide a systematic review and meta-analyses on the most clinically relevant obstetric and perinatal outcomes after use of donor sperm compared with partner sperm: hypertensive disorders of pregnancy, preeclampsia, low birth weight, and preterm birth. Our meta-analyses showed an increased risk for preeclampsia (pooled adjusted odds ratio (aOR) 1.77, 95% CI 1.26-2.48) and hypertensive disorders of pregnancy (pooled aOR 1.55, 95%, CI 1.20-2.00) in pregnancies resulting from IUI with donor sperm compared with IUI with partner sperm. No increased risk was seen for low birth weight or preterm birth after the use of donor sperm in IUI compared with the use of partner sperm in IUI. Subgroup analysis for singletons only did not change these results. The meta-analysis on low birth weight showed a lower risk after in IVF with donor sperm compared with IVF with partner sperm (pooled aOR 0.89, 95% CI 0.83-0.94). For hypertensive disorders of pregnancy, preeclampsia and preterm birth, no difference was found between IVF with donor sperm vs. partner sperm. Patients need to be informed about the moderately increased risk of hypertensive disorders of pregnancy and preeclampsia in pregnancies after IUI with donor sperm.

Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study.

OBJECTIVE: To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. DESIGN: A case-control study. SETTING: Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. POPULATION: We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. METHODS: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. MAIN OUTCOME MEASURES: Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. RESULTS: The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. TWEETABLE ABSTRACT: Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.

Imprinting disorders in children born after ART: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Is the risk of imprinting disorders increased in children conceived after ART? SUMMARY ANSWER: We found an adjusted odds ratio (AOR) of 2.84 [95% CI: 1.34-6.01] for Beckwith-Wiedemann syndrome in ART children, while the risk of Prader-Willi syndrome, Silver-Russell syndrome or Angelman syndrome was not increased in children conceived after ART. WHAT IS KNOWN ALREADY: Earlier studies, most of them small, have suggested an association between ART and imprinting disorders. STUDY DESIGN, SIZE, DURATION: This was a binational register-based cohort study. All children conceived by ART in Denmark (n = 45 393, born between 1994 and 2014) and in Finland (n = 29 244, born between 1990 and 2014) were identified. The full background populations born during the same time periods in the two countries were included as controls. Odds ratios of imprinting disorders in ART children compared with naturally conceived (NC) children were calculated. The median follow-up time was 8 years and 9 months for ART children and 11 years and 9 months for NC children. PARTICIPANTS/MATERIALS, SETTING, METHODS: From the national health registries in Denmark and Finland, we identified all children diagnosed with Prader-Willi syndrome (n = 143), Silver-Russell syndrome (n = 69), Beckwith-Wiedemann syndrome (n = 105) and Angelman syndrome (n = 72) born between 1994/1990 and 2014, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a total of 388 children diagnosed with imprinting disorders; 16 of these were conceived after ART. The overall AOR for the four imprinting disorders in ART children compared with NC children was 1.35 [95% CI: 0.80-2.29], but since eight ART children were diagnosed with Beckwith-Wiedemann syndrome, the AOR for this specific imprinting disorder was 2.84 [95% CI: 1.34-6.01]. The absolute risk of Beckwith-Wiedemann syndrome in children conceived after ART was still low: 10.7 out of 100 000 newborns. The risks of Prader-Willi syndrome, Silver-Russell syndrome and Angelman syndrome were not increased in children conceived after ART. LIMITATIONS, REASONS FOR CAUTION: Imprinting disorders are rare events and our results are based on few ART children with imprinting disorders. The aetiology is complex and only partly clarified, and the clinical diagnoses are challenged by a broad phenotypic spectrum. WIDER IMPLICATIONS OF THE FINDINGS: In the existing studies, results on the risk of imprinting disorders in children conceived after ART are ambiguous. This study adds that the risk of imprinting disorders in ART children is very small and perhaps restricted to Beckwith-Wiedemann syndrome. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (grant number: 71450), the Nordic Federation of Obstetrics and Gynecology (grant numbers: NF13041, NF15058, NF16026 and NF17043) and the Interreg Öresund-Kattegat-Skagerak European Regional Development Fund (ReproUnion project). The authors have no conflicts of interest related to this work. TRIAL REGISTRATION NUMBER: N/A.

The effect of low-dose aspirin on serum placental growth factor levels in a high-risk PREDO cohort.

OBJECTIVES: Our first aim was to study the longitudinal changes of serum placental growth factor (PlGF) concentration between 12+0 and 28+0 weeks of gestation in the prospective PREDO cohort. Our second aim was to study the effect of low-dose acetylsalicylic acid (LDA; 100 mg/day), started before the 14th week of gestation, on PlGF concentration. STUDY DESIGN: Blood samples were collected at 12+0-14+0, 18+0-20+0 and 26+0-28+0 weeks of gestation in 101 women without and 309 with clinical risk factors for pre-eclampsia. Risk-women were divided into two groups: to those who had medium risk for pre-eclampsia and to those who had high risk for pre-eclampsia. Finally there were seven groups according to risk, treatment (no prevention/placebo/LDA) and outcome measure pre-eclampsia. Longitudinal changes in the PlGF concentration between groups were compared. To investigate the effect of LDA on serum PlGF concentration, placebo (N = 62) and LDA (N = 61) groups were compared. A repeated measures ANOVA was used to analyze differences in PlGF levels between the groups. RESULTS: The increase in serum PlGF concentration was higher in LDA than in placebo group (time × group effect, p = 0.046). The increase in serum PlGF concentration during pregnancy was lower in high-risk women who had placebo and developed pre-eclampsia and in medium-risk women who developed pre-eclampsia compared to the other women (time × group effect, p < 0.001). There were no differences in PlGF change between low-risk women, medium-risk women who did not develop pre-eclampsia, high-risk women in the placebo group without pre-eclampsia and high-risk women in the LDA group with and without pre-eclampsia (p = 0.15). CONCLUSIONS: Our finding suggests an association between LDA started before 14 weeks of gestation and higher increase in serum PlGF concentration.

The effect of dietary counselling on food intakes in pregnant women at risk for gestational diabetes: a secondary analysis of a randomised controlled trial RADIEL.

BACKGROUND/OBJECTIVES: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM may be prevented by improving the diets of pregnant women. The objective of this study was to evaluate the effect of dietary counselling on the diets of pregnant women at GDM risk. SUBJECTS/METHODS: This study was a secondary analysis of a randomised controlled trial the Finnish gestational diabetes prevention study (RADIEL) in which pre-pregnant and pregnant women with previous GDM or BMI ⩾30 kg/m(2) were allocated into two groups, namely the control and the intervention groups. The control group received standard antenatal dietary counselling according to the Finnish Nutrition Recommendations. The intervention group participated in one individual dietary counselling session and one group dietary counselling session in addition to the standard counselling. This study included women who were recruited during pregnancy. To assess changes in food intake, food-intake questionnaires were collected during the first and the second trimester of pregnancy. Bootstrap type analysis of covariance was used, and 242 participants were included in the final analysis to study changes in food intake. RESULTS: The intakes of low-fat cheese (baseline adjusted mean 0.09 times/day; 95% confidence interval (CI) 0.07, 0.24; P=0.040) and fish (baseline adjusted mean 0.28 times per week; 95% CI 0.08, 0.49; P=0.011) showed a significant increase in the intervention group compared with the control group. CONCLUSIONS: This study showed that dietary counselling in early pregnancy can lead to modest dietary improvements in pregnant women at GDM risk.

Maternal depressive symptoms during pregnancy, placental expression of genes regulating glucocorticoid and serotonin function and infant regulatory behaviors.

BACKGROUND: Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and 'programming' of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors. METHOD: Bi-weekly self-ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 ± 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother-rated at 15.6 ± 4.2 days. RESULTS: Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13-0.69, p = 0.005], HSD1B11 (0.30, 0.03-0.57, p = 0.03), NR3C1 (0.44, 0.19-0.68, p = 0.001) and SLC6A4 (0.26, 0.00-0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05). CONCLUSIONS: Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors.

Maternal depressive symptoms throughout pregnancy are associated with increased placental glucocorticoid sensitivity.

BACKGROUND: Maternal prenatal depression predicts post-partum depression and increases risk of prematurity and low birth weight. These effects may be mediated by altered placental function. We hypothesized that placental function would be influenced by the gestational week of experiencing depressive symptoms and aimed to examine associations between maternal depressive symptoms during pregnancy and placental expression of genes involved in glucocorticoid and serotonin transfer between mother and fetus. METHOD: We studied women participating in a prospective pregnancy cohort: the Prediction and Prevention of Preeclampsia (PREDO) Study, Helsinki, Finland. Maternal depressive symptoms were assessed at 2-week intervals throughout pregnancy in 56 healthy women with singleton, term pregnancies. Messenger ribonucleic acid (mRNA) levels of glucocorticoid (GR) and mineralocorticoid (MR) receptors and serotonin transporter (SLC6A4), 11ß-hydroxysteroid dehydrogenase type 1 (HSD1) and 2 (HSD2) were quantified in placental biopsies. RESULTS: In adjusted analyses women who reported higher depressive symptoms across the whole pregnancy had higher mRNA levels of GR [effect size 0.31 s.d. units, 95% confidence interval (CI) 0.01-0.60, p = 0.042] and MR (effect size 0.34 s.d. units, 95% CI 0.01-0.68, p = 0.047). These effects were significant for symptoms experienced in the third trimester of pregnancy for GR; findings for MR were also significant for symptoms experienced in the second trimester. GR and MR mRNA levels increased linearly by having the trimester-specific depressive symptoms scores 0, 1 or 2-3 times above the clinical cut-off for depression (p = 0.003, p = 0.049, respectively, and p = 0.004, p = 0.15 in adjusted analyses). CONCLUSIONS: Our findings offer potential gestational-age-specific mechanisms linking maternal depressive symptoms during pregnancy via placental biology. Future studies will test whether these also link with adverse offspring outcomes.

First trimester hyperglycosylated human chorionic gonadotrophin in serum - a marker of early-onset preeclampsia.

INTRODUCTION: Recent studies indicate that treatment with low-dose aspirin may reduce the risk of preeclampsia. Thus, early prediction of preeclampsia is needed. Low serum concentrations of hyperglycosylated human chorionic gonadotrophin (hCG-h) are associated with early pregnancy loss. We therefore studied whether it may serve as an early marker of preeclampsia. METHODS: A nested case-control study included 158 women with subsequent preeclampsia, 41 with gestational hypertension, 81 normotensive women giving birth to small-for-gestational-age (SGA) infants and 427 controls participating in first trimester screening for Down's syndrome between 8 and 13 weeks of gestation. Gestational-age-adjusted multiples of medians (MoMs) were calculated for serum concentrations of hCG-h, the free beta subunit of hCG (hCGß) and pregnancy-associated plasma placental protein A (PAPP-A) and the proportion of hCG-h to hCG (%hCG-h). Clinical risk factors including mean arterial pressure (MAP) and parity were also included in the risk calculation. RESULTS: In women with subsequent preeclampsia %hCG-h was lower than in controls (median MoM 0.92, P < 0.001), especially in 29 cases with early-onset preeclampsia (0.86, P < 0.001), in which PAPP-A also was reduced (0.95, P = 0.001). At 90% specificity for prediction of early-onset preeclampsia, sensitivity was 56% (95% confidence interval, 52-61%) for %hCG-h, 33% (28-37%) for PAPP-A, and 69% (51-83%) for the combination of these with first trimester MAP and parity. The area under the receiver-operating characteristic (ROC) curve for the combination of all these was 0.863 (0.791-0.935). CONCLUSIONS: hCG-h is a promising first trimester marker for early-onset preeclampsia. Addition of PAPP-A and maternal risk factors may improve the results.

Blood pressure levels but not hypertensive complications have increased in Type 1 diabetes pregnancies during 1989-2010.

AIMS: The pre-pregnancy BMI and the third trimester HbA(1c) levels increased in Finnish parturients with Type 1 diabetes during 1989-2008. The aim of the present study was to investigate whether these trends have been accompanied by increases in blood pressure or hypertensive complications. Hypertension trends were analysed using the definitions of hypertension of both the American College of Obstetricians and Gynecologists and the American Diabetes Association. The associations of hypertension, as defined by the latter criteria, with perinatal complications were also studied. METHODS: The records of a cohort of 1007 consecutive patients with Type 1 diabetes with a singleton live childbirth during 1989-2010 at the Helsinki University Central Hospital were studied. RESULTS: The frequencies of hypertensive pregnancy complications did not change, but the mean diastolic blood pressure increased in normotensive parturients in all trimesters. The proportion of patients with systolic blood pressure > 130 mmHg or diastolic blood pressure > 80 mmHg in the first, second and third trimesters of pregnancy increased from 25 to 33%, from 26 to 35% and from 57 to 71%, respectively. Systolic blood pressure of 131-139 mmHg or diastolic blood pressure of 81-89 mmHg in the third trimester was associated with umbilical artery pH < 7.15. CONCLUSIONS: Blood pressure of patients with Type 1 diabetes during pregnancy is increasing. A growing proportion of women with Type 1 diabetes exceed the American Diabetes Association's definition of hypertension during pregnancy.

Maternal circulating PlGF concentrations and placenta-related pregnancy complications: First results from the CoLab AngF Study.

INTRODUCTION: Circulating angiogenic factors are potential markers for preeclampsia, but heterogeneous studies have failed to identify precise predictive/diagnostic properties. The Global CoLaboratory is investigating how to merge published data of angiogenic factors for meta-analysis on an individual sample basis. OBJECTIVE: To amalgamate pregnancy angiogenic factor studies, investigate diagnostic and predictive properties of these markers in preeclampsia and placenta-related pregnancy complications, and to test if measures from disparate platforms can be standardised. This is the first report using PlGF measures to diagnose preeclampsia. METHODS: Data were derived from 15 cohorts, within and outside the CoLaboratory network. Women were classified as either case (confirmed diagnosis of preeclampsia at sampling) or non-case (no preeclampsia at sampling). Individual PlGF measurements from four different analytical platforms were used, along with transformations of the data (e.g. log-transformations, transformations to a baseline platform). Transformed measurements were standardised both for specific platforms and globally, stratifying on gestational age. Different statistical techniques were compared. RESULTS: The database currently contains 1442 cases and 11,512 non-cases, which were used to define an algorithm to merge PlGF measurements from different platforms. Non-case distributions were used to standardise case results. Diagnostic PlGF measurements in relation to preeclampsia will be presented and confirm feasibility. CONCLUSIONS: Future studies can extend this approach to other angiogenic factors, prediction as well as diagnosis and to other placenta-related disorders.

Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials.

OBJECTIVE: To study the effect of aspirin in the prevention of pre-eclampsia in high-risk women. DESIGN: Randomised, double-blinded, placebo-controlled trial. SETTING: Maternity clinics in ten Finnish hospitals participating in the PREDO Project. SAMPLE: A total of 152 women with risk factors for pre-eclampsia and abnormal uterine artery Doppler velocimetry. METHODS: Participants were randomised to start either aspirin 100 mg/day or placebo at 12 + 0 to 13 + 6 weeks + days of gestation. Because of the limited power of this trial, we also conducted a meta-analysis of randomised controlled trials that included data on 346 women with abnormal uterine artery Doppler flow velocimetry, and aspirin 50-150 mg/day started at or before 16( ) weeks of gestation. MAIN OUTCOME MEASURE: Pre-eclampsia, gestational hypertension and birthweight standard deviation (SD) score. Outcome measures for the meta-analysis were pre-eclampsia, severe pre-eclampsia, preterm (diagnosed <37 + 0 weeks of gestation) and term pre-eclampsia. RESULTS: From the 152 randomised women, 121 were included in the final analysis. Low-dose aspirin did not reduce the rate of pre-eclampsia (relative risk [RR] 0.7, 95% CI 0.3-1.7); gestational hypertension (RR 1.6, 95% CI 0.6-4.2); early-onset pre-eclampsia (diagnosed <34 + 0 weeks of gestation) (RR 0.2, 95% CI 0.03-2.1); or severe pre-eclampsia (RR 0.4, 95% CI 0.1-1.3); and the results were not statistically significant in an intention-to-treat analysis. However, our meta-analysis, including the current data, suggested that low-dose aspirin initiated before 16 weeks of gestation reduces the risk of pre-eclampsia (RR 0.6, 95% CI 0.4-0.8) and severe pre-eclampsia (RR 0.3, 95% CI 0.1-0.7). CONCLUSIONS: Our trial showed no statistically significant effect of aspirin in preventing pre-eclampsia in high-risk women. However, our meta-analysis suggested that aspirin may reduce the incidence of pre-eclampsia.

OS009. Second trimester serum hyperglycosylated human chorionic gonadotrophin and preeclampsia.

INTRODUCTION: Hyperglycosylated human chorionic gonadotrophin (hCG-h), produced by the placental trophoblast cells, is involved in placental development in early pregnancy. Decreased second trimester urine hCG-h is associated with later preeclampsia, which may be a sign of impaired trophoblastic invasion preceding symptoms of the disease. OBJECTIVES: To study whether maternal second trimester serum hCG-h concentrations predict later development of preeclampsia. METHODS: Fifty-five women with subsequent preeclampsia, 21 women with gestational hypertension, 30 normotensive women with small-for-gestational-age (SGA) infants and 83 controls with uneventful pregnancies were included in the study. Their serum hCG and hCG-h concentrations were analyzed by fluoroimmunoassay at 14-17weeks of gestation. The proportion of hCG-h of total hCG (%hCG-h) was calculated and converted to multiples of the median (MoMs) of the controls. MoMs of the groups were compared by Mann-Whitney U test. Pearson's correlation was used to analyze correlations between clinical characteristics and serum marker concentrations. The results are given as medians with 95% confidence intervals (95% CI). A two-tailed P<0.05 was considered significant. RESULTS: The concentrations of hCG-h and %hCG-h decreased with advancing gestational weeks in women with subsequent preeclampsia (r=-0.289, p=0.032 and r=-0.464, p<0.001), but not in women in the other groups. There was a tendency towards lower concentrations of hCG-h and %hCG-h in women with subsequent preeclampsia than in controls. The median MoMs of %hCG-h were 0.89 (95% CI,0.79-1.00) in women with subsequent preeclampsia and 1.00 (0.91-1.11) in controls. The corresponding values for women with subsequent gestational hypertension were 1.00 (0.86-1.16), for those with subsequent SGA infants they were 1.09 (0.89-1.23). The difference between preeclampsia and the other groups together was significant (p=0.029). CONCLUSION: Earlier studies suggest that decreased urine hCG-h concentrations reflect changes in placental function that precede the development of preeclampsia. At 14-17weeks of gestation, the serum concentrations of hCG-h showed moderate validity to predict later development of preeclampsia. Further studies on the utility of hCG-h for prediction of subsequent preeclampsia are warranted.

OS066. Intrauterine CYP2J2 expression and circulatingepoxyeicosatrienoic acid levels in preeclampsia.

INTRODUCTION: The cytochrome P450 (CYP)-system regulates vascular functions, inflammation, and angiogenesis that are mechanistically important in preeclampsia. OBJECTIVES: The aim of this study was to analyze the dysregulation of the Cytochrome P450 in the pathogenesis of preeclampsia. METHODS: We performed microarray screening of placenta and decidua from 25 preeclamptic women and 23 controls. Results were confirmed by realtime RT-PCR, immunohistochemistry and Serum of patients were analyzed by HPLC tandem mass spectrometry. For functional testing we did cardiomyocyte contraction bioassay and myograph studies. The reduced uterine perfusion pressure (RUPP) rat model was proceed for interventional study. RESULTS: In microarray studies the CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic decidual tissue (3.9 fold, p<0.0001) and in preeclamptic placenta (1.55 fold, p<0.001). RT-PCR confirmed the upregulation and immunohistochemistry, localized CYP2J2 in trophoblasts of villi and deciduas at week 12 and term. The CYP2J2 metabolites were analyzed by HPLC tandem mass spectrometry. 5,6- epoxyeicosatrienoic acids (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids (DHET), were elevated in preeclamptic women compared to controls in the latter two-thirds of pregnancy and after delivery. Stimulation of the trophoblast-derived cell line SGHPL-4 with the preeclampsia-associated cytokine tumor necrosis factor-a enhanced CYP2J2 gene and protein expression. For functional testing, 5,6-EET increased the beating rate of neonatal cardiomyocytes in a bioassay and downregulated large-conductance calcium-activated potassium channel KCa 1.1 activity. In the RUPP rat model of preeclampsia, we observed elevated EET, DHET, and preeclamptic features that were ameliorated by the CYP inhibitor MsPPOH. Uterine arterial rings of rats also dilated in response to MsPPOH. CONCLUSION: Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction.

OS077. The chromosome 2q22 preeclampsia susceptibility locus reveals shared novel risk factors for CVD.

INTRODUCTION: We have previously localized a preeclampsia susceptibility locus on chromosome 2q22 in 34 Australian and New Zealand (AUS/NZL) families. Using an extended number of AUS/NZL families (n=74) we have now performed a comprehensive molecular genetics dissection of this locus. OBJECTIVES: Identify causal genetic risk factors for preeclampsia at the 2q22 risk locus. METHODS: To prioritize positional candidate genes for analysis we used a combination of bioinformatics, SNPing, whole-genome transcriptional profiling and proximity to the peak linkage signal. Prioritized genes were earmarked for exon-centric re-sequencing in 48 founder individuals from the 74 AUS/NZL families. All identified sequence variants were genotyped back in this extended familial cohort. Variants showing the strongest genetic association were genotyped in independent case-control cohorts from Australia (n=1095), Norway (n=3397) and Finland (n=1519), and in a large cohort of Mexican American families rich in quantitative cardiovascular disease (CVD) risk traits. RESULTS: We interrogated 1598 variants from 52 genes and identified four independent SNPs to be significantly associated with preeclampsia susceptibility in the 74 AUS/NZL families. These four SNPs reside in four novel preeclampsia candidate genes: LCT (rs2322659, p=0.002), LRP1B (rs35821928, p=0.0001), RND3 (rs115015150, p=0.002) and GCA (rs17783344, p=0.002). We could only replicate the LCT SNP association in the Australian case-control population (p=0.04, combined p=0.001). These four SNPs are however, significantly associated with several quantitative CVD risk traits such as oxidative stress indicators, inflammatory biomarkers and obesity risk factors. CONCLUSION: Previous independent studies have reported significant genetic associations with total cholesterol levels and obesity risk factors for variants within LCT and LRP1B, respectively. RND3 inhibits the biological activity of a downstream effector protein, ROCK, which is known to affect endothelial dysfunction, inflammation, oxidative stress and vascular re-modeling. Grancalcin (GCA) is known to impact the adhesive properties of fibronectin, a marker for endothelial vascular injury. To our knowledge, data from the current study present for the first time empirical evidence of possible shared genetic risk factors underlying both preeclampsia and other CVD-related traits.

PP009. A follow-up study of Finnish pre-eclampsia families identifies a new fetal susceptibility locus on chromosome 18.

INTRODUCTION: According to the epidemiological research both maternal and fetal genes influence in predisposition to pre-eclampsia (PE). We have previously detected linkage signals in Finnish families on chromosomes 2p25, 4q32, and 9p13 using maternal phenotypes. OBJECTIVES: Our aim was to perform a follow-up linkage analysis using updated maternal phenotypes and an unprecedented linkage analysis using fetal phenotypes. METHODS: We performed a non-parametric linkage analysis using the same sample set and microsatellite markers as reported in the original linkage study (Laivuori et al., [1]). Markers genotyped were available from 237 individuals in 15 Finnish families including 72 affected mothers (pregnancy complicated by PE n=54, eclampsia n=1, or gestational hypertension [GHT] n=17), and 49 affected fetuses (born from a pregnancy complicated by PE n=45, or GHT n=4). MERLIN software (Abecasis et al., 2002) was used for sample and marker quality control and linkage analysis. Results from this study were compared against the original results obtained by using GENEHUNTER 2.1 software. RESULTS: The maximum nonparametric linkage (NPL) scores on chromosome 2 were at 21.70cM near marker D2S168 using maternal and fetal phenotypes (NPL score 3.79, p=0.00008, and NPL score 2.95, p=0.002, respectively). On chromosome 4 the highest peak was at 158.20 cM near marker D4S413 using maternal phenotypes (NPL score 3.13 p=0.0009), and at 109.60 cM near marker D4S1572 using fetal phenotypes (NPL score 2.50, p=0.006). On chromosome 9 the highest peaks using maternal phenotypes were at 38.90cM near marker D9S169 (NPL=3.76, p=0.00008), and at 120.80 cM near marker D9S1811 (NPL=2.74, p=0.003). The maximum peak on chromosome 9 using fetal phenotypes was found at 59.20cM near marker D9S175 (NPL=2.69, p=0.004). We found a suggestive linkage on chromosome 18 at 86.80cM near marker D18S64 using fetal phenotypes (NPL score of 2.51, p=0.006), but the highest peak using maternal phenotypes did not reach significance. CONCLUSION: In this follow-up study we have confirmed the linkage signals identified in the original linkage analysis using maternal phenotypes. Linkage to chromosome 2 was also supported by analysis using fetal phenotypes. Chromosome 18 may harbour a new fetal susceptibility locus for PE.

Factor V Leiden as a risk factor for preterm birth--a population-based nested case-control study.

BACKGROUND: Preterm birth is a major cause of neonatal morbidity and mortality, occurring in 5-13% of deliveries in developed countries. Genetic thrombophilia can theoretically contribute to the induction of preterm delivery, but the role of thrombophilia as risk factor is unclear. OBJECTIVES: To assess factor V Leiden, FII G20210A and other selected inherited and acquired variables as risk factors for preterm birth. PATIENTS/METHODS: We performed a population-based nested case-control study of 100,000 consecutive pregnancies in Finland. Cases and controls were identified by combining national registers. Clinical data were obtained from medical records and standardized questionnaires. We studied 324 cases with preterm delivery at or after 22 and before 37 completed weeks of gestation, and 752 controls. RESULTS: FV Leiden was associated with a 2.4-fold risk (95% confidence interval [CI] 1.3-4.6) of preterm birth in all pregnancies, and a 2.6-fold risk (95% CI 1.4-5.1) in singleton pregnancies. FV Leiden was especially associated with late preterm birth at or after 32 weeks of pregnancy, with an odds ratio (OR) of 2.9 (95% CI 1.5-5.6) in all pregnancies and an OR of 3.1 (95% CI 1.6-6.2) in singleton pregnancies. FII G20210A was not associated with preterm birth. Twin pregnancy (OR 12.0, 95% CI 6.0-24.1) and a history of venous thrombosis (OR 3.8, 95% CI 1.4-9.8) were associated with increased risk. High educational level and modest overweight (body mass index 25-29.9 kg m(-2) ) had protective effects. CONCLUSIONS: Maternal carriage of FV Leiden was associated with increased risk of late but not early preterm birth. FII G20120A was not associated with preterm birth.