P. von Dadelszen

Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms‐like tyrosine kinase 1 and soluble endoglin in the prediction of pre‐eclampsia: a systematic review and meta‐analysis

Please cite this paper as: Kleinrouweler C, Wiegerinck M, Ris‐Stalpers C, Bossuyt P, van der Post J, von Dadelszen P, Mol B, Pajkrt E, for the EBM CONNECT Collaboration. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms‐like tyrosine kinase 1 and soluble endoglin in the prediction of pre‐eclampsia: a systematic review and meta‐analysis. BJOG 2012;119:778–787.

Maternal vitamin D status in pregnancy and adverse pregnancy outcomes in a group at high risk for pre-eclampsia.

Please cite this paper as: Shand A, Nassar N, Von Dadelszen P, Innis S, Green T. Maternal vitamin D status in pregnancy and adverse pregnancy outcomes in a group at high risk for pre‐eclampsia. BJOG 2010;117:1593–1598.

Decreased Placental Methylation at the H19/IGF2 Imprinting Control Region is Associated with Normotensive Intrauterine Growth Restriction but not Preeclampsia

UNLABELLED Many genes exhibiting genomic imprinting, parent-of-origin differences in gene expression, are involved in regulating placental and fetal growth. The goal of the present study was to assess whether abnormal regulation of imprinted genes is associated with intrauterine growth restriction (IUGR) and/or preeclampsia (PET). METHODS Genomic DNA was extracted from at least two whole villi samples from control (N=22), IUGR (N=13), PET (N=17), and PET+IUGR (N=21) placentas. Methylation was assessed using the Illumina GoldenGate Methylation Cancer Panel I array and Pyrosequencing and MS-SNuPE assays. RESULTS The 11p15.5 ICR1 (associated with H19 and IGF2) methylation showed considerable intra-placental variability. Nonetheless, average methylation at this site was significantly decreased in normotensive IUGR placentas (p<0.001), but not in any other group. Methylation at ICR2 (KvDMR1; associated with CDKN1C and other maternally expressed 11p15.5 genes) was not significantly altered in any group and no significant changes in expression levels were observed in the genes controlled by this region. There were no significant methylation changes observed in any candidate imprinted gene evaluated by the Illumina array. LINE-1 methylation, a marker of whole genome methylation, was also similar in all groups. CONCLUSIONS Reduced methylation of ICR1 is associated with normotensive IUGR but not IUGR associated with preeclampsia, suggesting a different etiology of IUGR in this group. A reduction in placental IGF2 could be an adaptive response to restrict fetal growth in the presence of abnormal placentation or a response to poor fetal growth itself.

Current CHS and NHBPEP Criteria for Severe Preeclampsia Do Not Uniformly Predict Adverse Maternal or Perinatal Outcomes

Objective: To determine the association between adverse maternal/perinatal outcomes and Canadian and U.S. preeclampsia severity criteria. Methods: Using PIERS data (Preeclampsia Integrated Estimate of RiSk), an international continuous quality improvement project for women hospitalized with preeclampsia, we examined the association between preeclampsia severity criteria and adverse maternal and perinatal outcomes (univariable analysis, Fishers exact test). Not evaluated were variables performed in <80% of pregnancies (e.g., 24-hour proteinuria). Results: Few of the evaluated variables were associated with adverse maternal (chest pain/dyspnea, thrombocytopenia, ‘elevated liver enzymes’, HELLP syndrome, and creatinine >110 μM) or perinatal outcomes (dBP >110 mm Hg and suspected abruption) (at p < 0.01). Conclusions: In the PIERS cohort, most factors used in the Canadian or American classifications of severe preeclampsia do not predict adverse maternal and/or perinatal outcomes. Future classification systems should take this into account.

Expectant Management of Severe Preeclampsia Remote from Term: A Structured Systematic Review

Objective: To compare outcomes associated with expectant vs. interventionist care of severe preeclampsia in observational studies. Data Sources: Medline (01/1980–07/2007), bibliographies of retrieved papers, personal files, Cochrane Database of Systematic Reviews. Study Selection: Expectant or interventionist care of preeclampsia at <34 wk. Tabulation, Integration, Results: Data abstraction independently by two reviewers. Median [IQR] of clinical maternal/perinatal outcomes presented. Results: 72 publications, primarily from tertiary care centres in Dutch and developed world sites. Expectant care of severe preeclampsia <34 wk (39 cohorts, 4,650 women), for which 40% of women are eligible, is associated with pregnancy prolongation of 7–14 d, and few serious maternal complications (median <5%), similar to interventionist care (2 studies, 42 women). Complication rates are higher with HELLP <34wk (12 cohorts, 438 women) and severe preeclampsia <28wk (6 cohorts, 305 women), similar to interventionist care (6 cohorts, 467 women and 2 cohorts, 70 women, respectively). Expectant care of HELLP <34 wk (12 cohorts, 438 women) is associated with fewer days gained (median 5), but more serious maternal morbidity (e.g., eclampsia, median 15%). More than half of women have at least temporary improvement of HELLP. In the developed world, expectant (vs. interventionist) care of severe preeclampsia or HELLP <34 wk is associated with reduced neonatal death and complications. Stillbirth is higher in Dutch and developing world sites where viability thresholds are higher. For preeclampsia <24wk (4 cohorts), perinatal mortality is >80%. No predictors of adverse maternal/perinatal outcomes were identified (13 studies). Conclusions: Future research should establish the best maternal/fetal monito regimen and indications for delivery with expectant care. A definitive RCT is needed.

The Control of Hypertension In Pregnancy Study pilot trial

Objective  To determine whether ‘less tight’ (versus ‘tight’) control of nonsevere hypertension results in a difference in diastolic blood pressure (dBP) between groups.

Low‐dose calcium supplementation for preventing pre‐eclampsia: a systematic review and commentary

Epidemiological data link low dietary calcium with pre‐eclampsia. Current recommendations are for 1.5–2 g/day calcium supplementation for low‐intake pregnant women, based on randomised controlled trials of ≥1 g/day calcium supplementation from 20 weeks of gestation. This is problematic logistically in low‐resource settings; excessive calcium may be harmful; and 20 weeks may be too late to alter outcomes.

Toll-like receptors 2 and 4 and the cryopyrin inflammasome in normal pregnancy and pre-eclampsia

Objective  Pre‐eclampsia involves a maternal inflammatory response that differs from both normal pregnancy and normotensive intrauterine growth restriction (IUGR). Our objective was to examine neutrophil Toll‐like receptor (TLR), cryopyrin, nuclear factor‐κB (NF‐κB) subunit and interleukin‐1β (IL‐1β), and inflammatory cytokine profiles in women with pre‐eclampsia or normotensive IUGR, as well as in normal pregnancy and non‐pregnancy controls.

Do Commonly Used Oral Antihypertensives Alter Fetal or Neonatal Heart Rate Characteristics? A Systematic Review

Objective: To examine fetal (FHR) and neonatal heart rate patterns following use of common oral antihypertensives in pregnancy. Methods: A systematic review of randomized controlled trials (RCTs), observational studies (N ≥ 6 women), and animal studies. Data were abstracted (two reviewers) to determine relative risk (RR) (or risk difference (RD) for low event rates) and 95% CI. Results: Eighteen RCTs (1858 women), one controlled observational study (N = 22), and seven case series (N = 117) were reviewed. Most hypertension was pregnancy‐induced (N = 14 studies). The FHR was assessed by cardiotocogram (CTG) (N = 17 studies (visual interpretation); 1 study (computerized CTG), or umbilical artery velocimetry (N = 4). Four studies examined neonatal heart rate. In placebo‐controlled RCTs (N = 192 women), adverse FHR effects did not differ between groups [9/101 (drugs) vs. 7/91 (placebo); RD 0.02, 95% CI (− 0.06, 0.11); χ2 = 1.02]. In six drug vs. drug RCTs (295 women), adverse FHR effects did not differ between groups [29/144 (methyldopa) vs. 42/151 (other drugs); RR 0.72, 95% CI (0.49, 1.07); χ2 = 0.69]. In one labetalol vs. placebo trial, neonatal bradycardia did not differ between groups [4/70 (labetalol) vs. 4/74 (placebo); OR 1.06, 95% CI (0.26, 4.39)], while in three drug vs. drug RCTs, neonatal bradycardia was not observed (0/24 vs. 0/26). Conclusions: Available data are inadequate to conclude whether oral methyldopa, labetalol, nifedipine, or hydralazine adversely affect fetal or neonatal heart rate and pattern. Until definitive data are available, FHR changes cannot be reliably attributed to drug effect, but may be due to progression of the underlying maternal or placental disease.

Toll-like Receptor-3 Stimulation Upregulates sFLT-1 Production by Trophoblast Cells

BACKGROUND Preeclampsia is characterized by a systemic inflammatory response involving cytokines, chemokines, and anti-angiogenic factors such as sFLT-1. In many other inflammatory diseases related responses are triggered by toll-like receptor (TLR) stimulation. Therefore, we tested the hypothesis that TLR stimulation of a trophoblast cell line induces inflammatory mediator production and, in particular, production of the preeclampsia-related anti-angiogenic factor sFLT-1. METHODS We stimulated human first trimester extravillous trophoblast cells (HTR-8/SV neo cell line) with a variety of TLR ligands and measured downstream NF-kappaB and IRF signaling, inflammatory mediator (RANTES), and sFLT-1 mRNA expression and protein production. RESULTS Of all TLR ligands, we found that TLR3 ligation with polyI:C resulted in the biggest response with 5.6-fold increased signaling via NF-kappaB and 5.8-fold increased signaling via IRF. RANTES mRNA expression increased 2900 fold and protein production increased 1600 fold in response to TLR3 ligation. sFLT-1 mRNA expression increased 1.7-fold and protein production increased 3.1-fold in response to TLR3 ligation. Inhibitors of the NF-kappaB and IRF signaling pathway decreased TLR3 ligation-induced sFLT-1 protein production by 31.8% and 24.9%, respectively. CONCLUSION We conclude that trophoblast cells respond to TLR3 ligation by signaling through both NF-kappaB and IRF pathways resulting in expression of inflammatory mediators and, in particular, the preeclampsia-related anti-angiogenic factor sFLT-1.