Matts Olovsson

Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia

BACKGROUND The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear. METHODS We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks. RESULTS In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3). CONCLUSIONS An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).

The risk of maternal ischaemic heart disease after gestational hypertensive disease

Objective  The aim of this study was to investigate whether the risk of developing ischaemic heart disease (IHD) later in life increases with severity and recurrence of gestational hypertensive disease.

Placental Growth Factor and Soluble FMS- Like Tyrosine Kinase-1 in Early-Onset and Late-Onset Preeclampsia

OBJECTIVE: To estimate whether alterations in plasma levels of the proangiogenic proteins placental growth factor (PlGF) and vascular endothelial growth factor-A (VEGF-A), and the antiangiogenic protein soluble fms-like tyrosine kinase-1 (sFlt1) were more pronounced in early-onset than in late-onset preeclampsia. METHODS: A cross-sectional study was conducted to estimate the levels of sFlt1, PlGF, and VEGF-A in plasma in a control group of nonpregnant women, in an early control group of women at 24–32 weeks of gestation, in a late control group of women at 36–42 weeks of gestation, and in cases of women with early-onset (before 32 weeks of gestation) and late-onset (after 35 weeks of gestation) preeclampsia. RESULTS: Women with early-onset preeclampsia had a 43 times higher median plasma sFlt1 level than early controls (P<.001). Women with late-onset preeclampsia had a three times higher median plasma sFlt1 level than late controls (P<.001). Women with early-onset preeclampsia had a 21 times lower median plasma PlGF level than early controls (P<.001). Women with late-onset preeclampsia had a five times lower median plasma PlGF level than late controls (P=.01). The median level of VEGF-A in plasma was less than 15 pg/mL in all groups of pregnant women. CONCLUSION: Both early- and late-onset preeclampsia are associated with altered plasma levels of sFlt1 and PlGF. The alterations are more pronounced in early-onset rather than in late-onset disease. LEVEL OF EVIDENCE: II

Antimüllerian Hormone Levels Are Strongly Associated With Live-Birth Rates After Assisted Reproduction

CONTEXT Previous studies have suggested that antimüllerian hormone (AMH) levels are positively associated with in vitro fertilization (IVF) outcome through their relationship with oocyte yield and not by reflecting oocyte or embryo quality. OBJECTIVE The aim was to investigate whether AMH levels are associated with pregnancy and live-birth rates and whether the results may also reflect qualitative aspects of oocytes and embryos. DESIGN The study was a prospective cohort study between April 2008 and June 2011. SETTING The study was done at a university-affiliated private infertility center. PATIENTS The study cohort consisted of 892 consecutive women undergoing 1230 IVF-intracytoplasmic sperm injection cycles. INTERVENTION(S) AMH levels, analyzed using the DSL ELISA kit, were statistically adjusted for repeated treatments and age and analyzed for associations with treatment outcome. MAIN OUTCOME MEASURES Pregnancy rates, live-birth rates, and stimulation outcome parameters were measured. RESULTS AMH was log-normally distributed with a mean (SD) of 2.3 (2.5) ng/mL. Live-birth rates per started cycle (mean [95% confidence interval]) increased log-linearly from 10.7% [7.2-14.1] for AMH < 0.84 ng/mL (25th percentile) to 30.8% [25.7-36.0] for AMH > 2.94 ng/mL (75th percentile), Ptrend < .0001, being superior in women with polycystic ovaries. These findings were significant also after adjustments were made for age and oocyte yield. AMH was also associated with ovarian response variables and embryo scores. CONCLUSIONS AMH is strongly associated with live-birth rates after IVF-intracytoplasmic sperm injection. AMH may therefore serve as a prognostic factor for the chance of a pregnancy and live birth. Treatment outcome was superior in patients with polycystic ovaries. The findings also indicate that AMH may partially comprise information about oocyte quality.

Long-term follow-up of patients with polycystic ovary syndrome: reproductive outcome and ovarian reserve

BACKGROUND The purpose of the present study was to examine long-term reproductive outcome and ovarian reserve in an unselected population of women with polycystic ovary syndrome (PCOS). METHODS A total of 91 patients with confirmed PCOS and 87 healthy controls were included in the study. Patients had been diagnosed between 1987 and 1995 and at the time of the follow-up, subjects were 35 years of age or older. RESULTS Among women who had attempted a pregnancy, 86.7% of PCOS patients and 91.6% of controls had given birth to at least one child. Among PCOS patients who had given birth, 73.6% had done so following a spontaneous conception. Mean ovarian volume and the number of antral follicles in PCOS patients were significantly greater than in control women (P < 0.001, respectively). PCOS patients also had higher serum concentrations of anti-Müllerian hormone and lower follicle-stimulating hormone levels. CONCLUSIONS Most women with PCOS had given birth, and the rate of spontaneous pregnancies was relatively high. Together with the ultrasound findings and the hormonal analyses, this finding could imply that PCOS patients have a good fecundity, and an ovarian reserve possibly superior to women with normal ovaries.

Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia

Based on gestational age at diagnosis and/or delivery, pre‐eclampsia (PE) is commonly divided into early‐onset (<34 weeks) and late‐onset (≥34 weeks) forms. Recently, the distinction between ‘placental’ and ‘maternal’ causation has been proposed, with ‘placental’ cases being more frequently associated with early‐onset and intrauterine growth restriction. To test whether molecular placental pathology varies according to clinical presentation, we investigated stress‐signalling pathways, including unfolded protein response (UPR) pathways, MAPK stress pathways, heat‐shock proteins and AMPKα in placentae delivered by caesarean section for clinical indications at different gestational ages. Controls included second‐trimester, pre‐term and normal‐term placentae. BeWo cells were used to investigate how these pathways react to different severities of hypoxia–reoxygenation (H/R) and pro‐inflammatory cytokines. Activation of placental UPR and stress‐response pathways, including P‐IRE1α, ATF6, XBP‐1, GRP78 and GRP94, P‐p38/p38 and HSP70, was higher in early‐onset PE than in both late‐onset PE and normotensive controls (NTCs), with a clear inflection around 34 weeks. Placentae from ≥ 34 weeks PE and NTC were indistinguishable. Levels of UPR signalling were similar between second‐trimester and term controls, but were significantly higher in pre‐term ‘controls’ delivered vaginally for chorioamnionitis and other conditions. Severe H/R (1/20% O2) induced equivalent activation of UPR pathways, including P‐eIF2α, ATF6, P‐IRE1α, GRP78 and GRP94, in BeWo cells. By contrast, the pro‐inflammatory cytokines TNFα and IL‐1β induced only mild activation of P‐eIF2α and GRP78. AKT, a central regulator of cell proliferation, was reduced in the < 34 weeks PE placentae and severe H/R‐treated cells, but not in other conditions. These findings provide the first molecular evidence that placental stress may contribute to the pathophysiology of early‐onset pre‐eclampsia, whereas that is unlikely to be the case in the late‐onset form of the syndrome.

Immunological Aspects of Endometriosis: An Update

Citation Olovsson M. Immunological Aspects of Endometriosis: An Update. Am J Reprod Immunol 2011; 66 (Suppl. 1): 101–104

Angiopoietin-1/Angiopoietin-2 Ratio for Prediction of Preeclampsia

BACKGROUND A number of different biophysical and biochemical markers have been proposed as predictors of preeclampsia. Factors involved in the angiogenic balance are suggested as candidate markers. The purpose of this prospective, longitudinal cohort study was to determine whether a ratio between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) can be used to predict preeclampsia in a low-risk population. METHODS A cohort of healthy pregnant women (n = 469) were enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37. By using commercially available enzyme-linked immunosorbent assay kits Ang-1 and Ang-2 were analyzed. RESULTS The median Ang-1/Ang-2 ratio increased during pregnancy in all women, but the ratios were significantly lower at gestational weeks 25 and 28 in women who later developed preeclampsia than in normal pregnant women (1.49 compared to 2.19 and 2.12 compared to 3.54, P < 0.05 and P < 0.05). CONCLUSION Our data indicate that in a low-risk population of women the Ang-1/Ang-2 ratio in plasma constitutes a possible biomarker for prediction of later onset of preeclampsia.

Diabetes and impaired glucose tolerance in patients with polycystic ovary syndrome—a long term follow-up

BACKGROUND The overall risk of developing diabetes mellitus and glucose intolerance seems to be higher in women with polycystic ovary syndrome (PCOS) than in healthy women. The aim of this long-term follow-up study was to examine glucose tolerance and insulin sensitivity in middle-aged women previously diagnosed with PCOS in comparison with age-matched healthy controls. METHODS Women diagnosed with PCOS between 1987 and 1995 were invited to participate in the study. A total of 84 PCOS patients and 87 control subjects participated. Anthropometric (BMI, waist/hip ratio) and metabolic parameters (oral glucose tolerance test) were measured. Insulin sensitivity was expressed by the Matsuda index and beta cell function by the insulinogenic index. PCOS women were subgrouped according to phenotype at the index assessment (with or without hyperandrogenism) and persistence of PCOS symptoms at the follow-up (persisting or resolved PCOS). RESULTS Eighteen (21.4%) PCOS patients and four (4.5%) controls had developed type 1 or type 2 diabetes or impaired glucose tolerance (IGT) at the follow-up investigation (P < 0.05). Matsuda insulin sensitivity index was lower and the insulinogenic index was increased in women with previously diagnosed PCOS compared with control subjects. In addition, PCOS patients with or without hyperandrogenism, and PCOS patients with persisting and resolved PCOS all had lower Matsuda insulin sensitivity index and increased insulinogenic index in comparison with controls. CONCLUSIONS IGT and type 2 diabetes occurred more often in PCOS patients. Independent on PCOS phenotype at index assessment and persistence of PCOS symptoms at the follow-up investigation, women with PCOS had lower insulin sensitivity but a well-preserved beta cell function in comparison with control subjects.

Cadmium chloride alters mRNA levels of angiogenesis related genes in primary human endometrial endothelial cells grown in vitro.

Cadmium, is known to cause adverse reproductive effects, and classified as an endocrine disrupting chemical (EDC). Human endometrial endothelial cells (HEEC) have a key role in the regulation of endometrial angiogenesis. These cells are known to express estrogen receptors, a feature that makes them potential targets for EDCs such as cadmium. We have designed a co-culture system, in which HEEC were grown in the same cell culture medium as endometrial stromal cells but in separate, communicating chambers. With quantitative PCR, we investigated changes in mRNA expression of genes associated with angiogenesis, sex steroids and endothelial cell specific functions. We found that cadmium altered the mRNA expression of the two important angiogenic molecules VEGF-A and PLGF. Cadmium might thus affect endometrial angiogenesis and as a consequence cause endometrial dysfunction with an increased risk for fertility problems.