Joris A. M. van der Post

Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review

BACKGROUND Thyroid dysfunction and thyroid autoimmunity are prevalent among women of reproductive age and are associated with adverse pregnancy outcomes. Preconception or early pregnancy screening for thyroid dysfunction has been proposed but is not widely accepted. We conducted a systematic review of the literature on the clinical significance of thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy. METHODS Relevant studies were identified by searching Medline, EMBASE and the Cochrane Controlled Trials Register. RESULTS From a total of 14 208 primary selected titles, 43 articles were included for the systematic review and 38 were appropriate for meta-analyses. No articles about hyperthyroidism were selected. Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, was associated with the occurrence of pre-eclampsia [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1-2.6] and an increased risk of perinatal mortality (OR 2.7, 95% CI 1.6-4.7). In the meta-analyses, the presence of thyroid antibodies was associated with an increased risk of unexplained subfertility (OR 1.5, 95% CI 1.1-2.0), miscarriage (OR 3.73, 95% CI 1.8-7.6), recurrent miscarriage (OR 2.3, 95% CI 1.5-3.5), preterm birth (OR 1.9, 95% CI 1.1-3.5) and maternal post-partum thyroiditis (OR 11.5, 95% CI 5.6-24) when compared with the absence of thyroid antibodies. CONCLUSIONS Pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality and (recurrent) miscarriage. Future research, within the setting of clinical trials, should focus on the potential health gain of identification, and effect of treatment, of thyroid disease on pregnancy outcome.

Accuracy of mean arterial pressure and blood pressure measurements in predicting pre-eclampsia: systematic review and meta-analysis

Objective To determine the accuracy of using systolic and diastolic blood pressure, mean arterial pressure, and increase of blood pressure to predict pre-eclampsia. Design Systematic review with meta-analysis of data on test accuracy. Data sources Medline, Embase, Cochrane Library, Medion, checking reference lists of included articles and reviews, contact with authors. Review methods Without language restrictions, two reviewers independently selected the articles in which the accuracy of blood pressure measurement during pregnancy was evaluated to predict pre-eclampsia. Data were extracted on study characteristics, quality, and results to construct 2×2 tables. Summary receiver operating characteristic curves and likelihood ratios were generated for the various levels and their thresholds. Results 34 studies, testing 60 599 women (3341 cases of pre-eclampsia), were included. In women at low risk for pre-eclampsia, the areas under the summary receiver operating characteristic curves for blood pressure measurement in the second trimester were 0.68 (95% confidence interval 0.64 to 0.72) for systolic blood pressure, 0.66 (0.59 to 0.72) for diastolic blood pressure, and 0.76 (0.70 to 0.82) for mean arterial pressure. Findings for the first trimester showed a similar pattern. Second trimester mean arterial pressure of 90 mm Hg or more showed a positive likelihood ratio of 3.5 (95% confidence interval 2.0 to 5.0) and a negative likelihood ratio of 0.46 (0.16 to 0.75). In women deemed to be at high risk, a diastolic blood pressure of 75 mm Hg or more at 13 to 20 weeks’ gestation best predicted pre-eclampsia: positive likelihood ratio 2.8 (1.8 to 3.6), negative likelihood ratio 0.39 (0.18 to 0.71). Additional subgroup analyses did not show improved predictive accuracy. Conclusion When blood pressure is measured in the first or second trimester of pregnancy, the mean arterial pressure is a better predictor for pre-eclampsia than systolic blood pressure, diastolic blood pressure, or an increase of blood pressure.

Foley catheter versus vaginal prostaglandin E2 gel for induction of labour at term (PROBAAT trial): an open-label, randomised controlled trial

BACKGROUND Induction of labour is a common obstetric procedure. Both mechanical (eg, Foley catheters) and pharmacological methods (eg, prostaglandins) are used for induction of labour in women with an unfavourable cervix. We aimed to compare the effectiveness and safety of induction of labour with a Foley catheter with induction with vaginal prostaglandin E2 gel. METHODS We did an open-label, randomised controlled trial in 12 hospitals in the Netherlands between Feb 10, 2009, and May 17, 2010. We enrolled women with a term singleton pregnancy in cephalic presentation, intact membranes, an unfavourable cervix, an indication for induction of labour, and no prior caesarean section. Participants were randomly allocated by an online randomisation system to induction of labour with a 30 mL Foley catheter or vaginal prostaglandin E2 gel (1:1 ratio). Because of the nature of the intervention this study was not blinded. The primary outcome was caesarean section rate. Secondary outcomes were maternal and neonatal morbidity and time from intervention to birth. All analyses were done on an intention-to-treat basis. We also did a meta-analysis that included our trial. The trial was registered with the Dutch trial registry, number NTR 1646. FINDINGS 824 women were allocated to induction of labour with a Foley catheter (n=412) or vaginal prostaglandin E2 gel (n=412). Caesarean section rates were much the same between the two groups (23%vs 20%, risk ratio [RR] 1·13, 95% CI 0·87-1·47). A meta-analysis including our trial data confirmed that a Foley catheter did not reduce caesarean section rates. We recorded two serious maternal adverse events, both in the prostaglandin group: one uterine perforation and one uterine rupture. INTERPRETATION In women with an unfavourable cervix at term, induction of labour with a Foley catheter is similar to induction of labour with prostaglandin E2 gel, with fewer maternal and neonatal side-effects. FUNDING None.

Extensive platelet activation in preeclampsia compared with normal pregnancy: Enhanced expression of cell adhesion molecules

OBJECTIVES Platelets play an important role in the pathophysiologic mechanisms of preeclampsia. Our purpose was to investigate by means of flow cytometry to what extent platelets circulate in an activated state during normal pregnancy and whether this activation is more extensive in preeclampsia. STUDY DESIGN Platelets in whole blood from 10 preeclamptic third-trimester pregnant women (highest diastolic blood pressure range 100 to 130 mm Hg, proteinuria range 0.59 to 11.5 gm/24 hr) and from 10 normotensive third-trimester pregnant controls were analyzed with the following activation markers: anti-P-selectin (alpha-granule secretion), anti-CD63 (lysosomal secretion), PAC-1 (monoclonal antibody against fibrinogen receptor conformation of the glycoprotein IIb/IIIa complex), anti-platelet endothelial cell adhesion molecule-1, and annexin-V (a placental protein that binds to negatively charged phospholipids, present on the outside of the platelet plasma membrane after activation). The differences in surface antigen exposure between the two groups were determined by double-label flow cytometry. Flow cytometric data were analyzed in two ways: first, the percentages of activated platelets above a certain threshold compared with a nonpregnant control sample were determined, indicative for activation of a subpopulation of cells, and, second, the mean fluorescence intensities were determined, indicative of the mean surface antigen expression of the total platelet population. RESULTS Analysis of the percentage of activated platelets proved most informative. With this analysis an enhanced platelet activation status was present in 4 of 10 normotensive patients and a more extensive platelet activation status in all 10 preeclamptic patients, as indicated by P-selectin (p = 0.008) and CD63 (p = 0.03) expression. Increased platelet endothelial cell adhesion molecule-1 (p = 0.005) expression was also observed in preeclampsia. CONCLUSIONS Flow cytometric analysis clearly indicated that platelets circulate in a more extensively activated state during preeclampsia than during normal pregnancy. The increased platelet endothelial cell adhesion molecule-1 expression in preeclamptic patients demonstrates that, besides alpha-granular and lysosomal release, other hitherto unknown mechanisms are involved. Platelet endothelial cell adhesion molecule-1 appears to be the best marker to distinguish preeclamptic patients from normotensive pregnant women. Only a subpopulation of the platelets appears to be activated.

Neonatal outcome following elective cesarean section beyond 37 weeks of gestation: a 7-year retrospective analysis of a national registry.

OBJECTIVE We sought to evaluate number and timing of elective cesarean sections at term and to assess perinatal outcome associated with this timing. STUDY DESIGN We conducted a recent retrospective cohort study including all elective cesarean sections of singleton pregnancies at term (n = 20,973) with neonatal follow-up. Primary outcome was defined as a composite of neonatal mortality and morbidity. RESULTS More than half of the neonates were born at <39 weeks of gestation, and they were at significantly higher risk for the composite primary outcome than neonates born thereafter. The absolute risks were 20.6% and 12.5% for birth at <38 and 39 weeks, respectively, as compared to 9.5% for neonates born > or = 39 weeks. The corresponding adjusted odds ratios (95% confidence interval) were 2.4 (2.1-2.8) and 1.4 (1.2-1.5), respectively. CONCLUSION More than 50% of the elective cesarean sections are applied at <39 weeks, thus jeopardizing neonatal outcome.

Changes in Microparticle Numbers and Cellular Origin During Pregnancy and Preeclampsia

Background: Microparticles (MP) are pro-coagulant vesicles derived from various cells. Evidence is accumulating that MP are of pathophysiological relevance in autoimmune, cardiovascular, and thromboembolic diseases and inflammatory disorders. Therefore, their role in the development of preeclampsia was investigated and MP from preeclamptic patients influenced endothelial-dependent vasodilatation. Knowledge about changes in circulating MP numbers during pregnancy and preeclampsia is lacking. We determined this longitudinally and investigated whether these numbers related to the severity of preeclampsia. Methods: Samples were obtained from pregnant women and preeclamptic patients during pregnancy and postpartum. MP were isolated and studied by flow cytometry. Results: During pregnancy, MP were decreased at 12 weeks gestation and then returned to postpartum values. In patients with preeclampsia, MP numbers were reduced at 28 and 36 weeks (both p = 0.04). Monocyte-derived MP were elevated in preeclampsia at 28 (p = 0.007), 32 (p = 0.02), and 36 weeks (p = 0.01), as were erythrocyte-derived MP at 28 weeks (p = 0.04). Placenta-derived MP increased in pregnancy and preeclampsia. During pregnancy, a correlation was present between placenta-derived MP and systolic blood pressure (r = 0.33, p = 0.015). No other correlations were found. Conclusions: During pregnancy, numbers of MP initially decrease and subsequently normalize. Placenta-derived MP increase, possibly because of placental growth. In preeclampsia, reduced numbers of PMP are due to decreased platelet counts. Increased numbers of monocyte-derived MP reflect monocyte activation, which may be an expression of the systemic inflammation in preeclampsia. Lack of correlation between numbers of MP and severity of preeclampsia suggests that MP numbers alone do not explain the reported vascular effects of MP.

Serum screening with Down's syndrome markers to predict pre-eclampsia and small for gestational age: Systematic review and meta-analysis

BackgroundReliable antenatal identification of pre-eclampsia and small for gestational age is crucial to judicious allocation of monitoring resources and use of preventative treatment with the prospect of improving maternal/perinatal outcome. The purpose of this systematic review was to determine the accuracy of five serum analytes used in Downs serum screening for prediction of pre-eclampsia and/or small for gestational age.MethodsThe data sources included Medline, Embase, Cochrane library, Medion (inception to February 2007), hand searching of relevant journals, reference list checking of included articles, contact with experts. Two reviewers independently selected the articles in which the accuracy of an analyte used in Downss serum screening before the 25th gestational week was associated with the occurrence of pre-eclampsia and/or small for gestational age without language restrictions. Two authors independently extracted data on study characteristics, quality and results.ResultsFive serum screening markers were evaluated. 44 studies, testing 169,637 pregnant women (4376 pre-eclampsia cases) and 86 studies, testing 382,005 women (20,339 fetal growth restriction cases) met the selection criteria. The results showed low predictive accuracy overall. For pre-eclampsia the best predictor was inhibin A>2.79MoM positive likelihood ratio 19.52 (8.33,45.79) and negative likelihood ratio 0.30 (0.13,0.68) (single study). For small for gestational age it was AFP>2.0MoM to predict birth weight < 10th centile with birth < 37 weeks positive likelihood ratio 27.96 (8.02,97.48) and negative likelihood ratio 0.78 (0.55,1.11) (single study). A potential clinical application using aspirin as a treatment is given as an example.There were methodological and reporting limitations in the included studies thus studies were heterogeneous giving pooled results with wide confidence intervals.ConclusionDowns serum screening analytes have low predictive accuracy for pre-eclampsia and small for gestational age. They may be a useful means of risk assessment or of use in prediction when combined with other tests.

Are tests for predicting pre-eclampsia good enough to make screening viable? A review of reviews and critical appraisal

The aim of this article is to review the accuracy of tests purported to be predictive of pre‐eclampsia, a major cause of maternal and perinatal mortality and morbidity worldwide. A review of systematic reviews was done. A total of 219 studies were evaluated for the accuracy of 27 tests for predicting pre‐eclampsia. Study quality assessment and data abstraction were performed using piloted proformas. Bivariate meta‐analyses were used to synthesize data. Levels of sensitivity and specificity were measured. There were deficiencies in many areas of methodology including blinding, test description, and reference standard adequacy. No test had a high level of both sensitivity and specificity of greater than 90%. Where multiple studies were available, only BMI > 34, alpha‐fetoprotein, fibronectin (cellular and total), and uterine artery Doppler (bilateral notching) measurements reached specificity above 90%. Only Doppler (any/unilateral notching, resistance index, and combinations) measurements were over 60% sensitive. Studies were of variable quality and most tests performed poorly. Further research should focus on tests which offer much higher levels of sensitivity than tests currently available. High sensitivity is a more useful attribute in early detection of pre‐eclampsia than specificity because consideration of benefits, harms and costs indicates a much greater preference for minimizing false negatives than false positives, although the ideal would be to avoid both.

Microparticles and exosomes: impact on normal and complicated pregnancy.

Eukaryotic cells release vesicles into their environment by membrane shedding (ectosomes or microparticles) and secretion (exosomes). Microparticles and exosomes occur commonly in vitro and in vivo. The occurrence, composition and function(s) of these vesicles change during disease (progression). During the last decade, the scientific and clinical interest increased tremendously. Evidence is accumulating that microparticles and exosomes may be of pathophysiological relevance in autoimmune, cardiovascular and thromboembolic diseases, as well as inflammatory and infectious disorders. In this review, we will summarize the discovery, biology, structure and function of microparticles and exosomes, and discuss their (patho‐) physiological role during normal and complicated pregnancy.

Clinical factors to predict the outcome of external cephalic version : a metaanalysis

OBJECTIVE The objective of the study was to systematically review the medical literature reporting on potential clinical prognosticators for the outcome of external cephalic version (ECV). STUDY DESIGN Medline, EMBASE, and Cochrane Central Register of Controlled Trials were searched. Studies reporting on potential clinical prognosticators and ECV success rates that allowed construction of a 2 x 2 table were selected. RESULTS We detected 53 primary articles reporting on 10,149 women. Multiparity (P >/= 1.00; odds ratio [OR], 2.5; 95% confidence interval [CI], 2.3-2.8), nonengagement of the breech (OR, 9.4; 95% CI, 6.3-14), a relaxed uterus (OR, 18; 95% CI, 12-29), a palpable fetal head (OR, 6.3; 95% CI, 4.3-9.2), and maternal weight less than 65 kg (OR, 1.8; 95% CI, 1.2-2.6) were predictors for successful external cephalic version. CONCLUSION Success of an ECV attempt is associated with clinical factors. This should be taken into account in the counseling of women prior to an ECV attempt.