Preventing preterm birth with progesterone: costs and effects of screening low risk women with a singleton pregnancy for short cervical length, the Triple P study

Contains fulltext : 97255.pdf (postprint version ) (Open Access)BACKGROUND: Women with a short cervical length in mid-trimester pregnancy have a higher risk of preterm birth and therefore a higher rate of neonatal mortality and morbidity. Progesterone can potentially decrease the number of preterm births and lower neonatal mortality and morbidity. Previous studies showed good results of progesterone in women with either a history of preterm birth or a short cervix. However, it is unknown whether screening for a short cervix and subsequent treatment in mid trimester pregnancy is effective in low risk women. METHODS/DESIGN: We plan a combined screen and treat study among women with a singleton pregnancy without a previous preterm birth. In these women, we will measure cervical length at the standard anomaly scan performed between 18 and 22 weeks. Women with cervical length </= 30 mm at two independent measurements will be randomly allocated to receive either vaginal progesterone tablets or placebo between 22 and 34 weeks. The primary outcome of this trial is adverse neonatal condition, defined as a composite outcome of neonatal mortality and severe morbidity. Secondary outcomes are time to delivery, preterm birth rate before 32, 34 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We will assess growth, physical condition and neurodevelopmental outcome of the children at two years of age. DISCUSSION: This study will provide evidence for the usefulness and cost-effectiveness of screening for short cervical length at the 18-22 weeks and subsequent progesterone treatment among low risk women. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR207

Who is (not) at risk? Prognostic tests and models in obstetrics with a focus on pre-eclampsia and preterm birth

Effective and efficient care relies on accurate and individualized estimates of risk that a certain health outcome (favourable or unfavourable) occurs. Thereby only those patients who are at high risk for an outcome can be selected to undergo a procedure or to receive (preventive) treatment or intervention. Prognostic factors, or more than one factor combined in a multivariable model, can be used to estimate such risks. This thesis (1) gives an overview of available prediction models in obstetrics and how well they could or should be used in the context of current evidence; (2) evaluates the potential of risk changes over time to predict complications of pre-eclampsia with the use of an existing model; (3) synthesizes available evidence for commonly investigated biomarkers for pre-eclampsia and those that warrant further investigation for potential use as a biomarker; (4) investigates the ability of combinations of patient characteristics and ultrasound to differentiate between women at low and high risk for pre-eclampsia or recurrent preterm birth; and (5) assesses a previously reported association between CRL and preterm birth to evaluate its potential role in predicting spontaneous preterm birth. It is our impression that so far, efforts to predict outcomes in obstetrics have not moved far beyond the development phase. We did not find evidence that any test or prediction model described here would improve clinical outcomes. At this stage we cannot advise a new model or test that should be used in clinical practice. We encourage researchers to perform external validation and impact studies

Which second trimester placenta previa remains a placenta previa in the third trimester: A prospective cohort study

Objective: The far majority of women with a placenta previa in the second trimester will no longer have a placenta that overlies the internal os in the third trimester. Women with a placenta previa in the third trimester are at risk for complication such as preterm birth and blood loss. Four counselling purposes we aim to identify which women with a second trimester placenta previa have a low-risk and a high-risk for persistence of the placenta previa. Study design: A prospective cohort study of women with a placenta previa in the second trimester between 2014 and 2019. The odds for having a placenta previa in the third trimester were calculated for different baseline characteristics. Multilevel likelihood ratios for ranges of the placenta overlying the internal os in the second trimester and the corresponding ROC curve were calculated to identify the optimal cut-off values. Results: We included 313 women with a placenta previa in the second trimester. The placenta was more frequently located on the posterior wall (62 %) than on the anterior wall (38 %). At evaluation in the third trimester, 37 women (14 %) still had a placenta previa. Women with a larger distance of the placenta overlying the internal os, women having a previous cesarean delivery and women after a conception with assisted reproductive technique had a significant higher risk of placenta previa persistence (p-values <0.001). Women with a placenta overlying less than 14 mm can be considered as low-risk, indicated by a likelihood ratio of 0. Women with a placenta with more than 55 mm overlap can be considered as high-risk, indicated a the likelihood ratio of ∞. Conclusion: The majority of the second trimester placenta previa will no longer overly the internal os in the third trimester. Placenta previa persistence is associated with the distance overlying the internal os, a previous cesarean delivery and assisted reproductive techniques. In the second trimester, women can be identified as low-risk and high-risk for persistence of placenta previa. This can be used for risk stratification, counselling and individualized care for women with a second trimester placenta previa

Which second trimester placenta previa remains a placenta previa in the third trimester: A prospective cohort study

Objective: The far majority of women with a placenta previa in the second trimester will no longer have a placenta that overlies the internal os in the third trimester. Women with a placenta previa in the third trimester are at risk for complication such as preterm birth and blood loss. Four counselling purposes we aim to identify which women with a second trimester placenta previa have a low-risk and a high-risk for persistence of the placenta previa. Study design: A prospective cohort study of women with a placenta previa in the second trimester between 2014 and 2019. The odds for having a placenta previa in the third trimester were calculated for different baseline characteristics. Multilevel likelihood ratios for ranges of the placenta overlying the internal os in the second trimester and the corresponding ROC curve were calculated to identify the optimal cut-off values. Results: We included 313 women with a placenta previa in the second trimester. The placenta was more frequently located on the posterior wall (62 %) than on the anterior wall (38 %). At evaluation in the third trimester, 37 women (14 %) still had a placenta previa. Women with a larger distance of the placenta overlying the internal os, women having a previous cesarean delivery and women after a conception with assisted reproductive technique had a significant higher risk of placenta previa persistence (p-values <0.001). Women with a placenta overlying less than 14 mm can be considered as low-risk, indicated by a likelihood ratio of 0. Women with a placenta with more than 55 mm overlap can be considered as high-risk, indicated a the likelihood ratio of ∞. Conclusion: The majority of the second trimester placenta previa will no longer overly the internal os in the third trimester. Placenta previa persistence is associated with the distance overlying the internal os, a previous cesarean delivery and assisted reproductive techniques. In the second trimester, women can be identified as low-risk and high-risk for persistence of placenta previa. This can be used for risk stratification, counselling and individualized care for women with a second trimester placenta previa

Prenatal sonographic features can accurately determine parental origin in triploid pregnancies

Objective: To describe the prenatal sonographic features and maternal biochemical markers in triploid pregnancies and to assess whether prenatal phenotype can determine genetic origin. Methods: We performed a retrospective multicenter cohort study that included all triploid pregnancies diagnosed between 2000 and 2018 in two Fetal Medicine Units in Amsterdam. Fetal growth, presence of structural anomalies, extra-fetal anomalies, and maternal biochemical markers were retrieved. Asymmetrical intrauterine growth restriction was diagnosed when the head-to-abdominal circumference (HC/AC) ratio was >95th centile. Parental origin was analyzed via molecular genotyping in 46 cases (38.3%). Results: One hundred and twenty triploid pregnancies were identified, of which 86 cases (71.6%) were detected before 18 weeks of gestation. Triploidy of maternal origin was found in 32 cases (69.6%) and was associated with asymmetrical growth restriction, a thin placenta, and low pregnancy-associated plasma protein A and free beta-human chorionic gonadotrophin (β-hCG) levels. Triploidy of paternal origin was found in 14 cases (30.4%) and was associated with an increased nuchal translucency, placental molar changes, and a high free β-hCG. Prospective prediction of the parental origin of the triploidy was made in 30 of the 46 cases based on phenotypical ultrasound presentation, and it was correct in all cases. Conclusion: Asymmetrical growth restriction with severe HC/AC discrepancy is pathognomonic of maternal triploidy. Placental molar changes indicate a paternal triploidy. Moreover, triploidy can present with an abnormal first trimester combined test, with serum levels on the extreme end. When available results of maternal serum markers can support the diagnosis of parental origin of the triploidy, an accurate assessment of the parental origin based on prenatal sonographic features is possible, making DNA analysis redundant

Prenatal sonographic features can accurately determine parental origin in triploid pregnancies

Objective: To describe the prenatal sonographic features and maternal biochemical markers in triploid pregnancies and to assess whether prenatal phenotype can determine genetic origin. Methods: We performed a retrospective multicenter cohort study that included all triploid pregnancies diagnosed between 2000 and 2018 in two Fetal Medicine Units in Amsterdam. Fetal growth, presence of structural anomalies, extra-fetal anomalies, and maternal biochemical markers were retrieved. Asymmetrical intrauterine growth restriction was diagnosed when the head-to-abdominal circumference (HC/AC) ratio was >95th centile. Parental origin was analyzed via molecular genotyping in 46 cases (38.3%). Results: One hundred and twenty triploid pregnancies were identified, of which 86 cases (71.6%) were detected before 18 weeks of gestation. Triploidy of maternal origin was found in 32 cases (69.6%) and was associated with asymmetrical growth restriction, a thin placenta, and low pregnancy-associated plasma protein A and free beta-human chorionic gonadotrophin (β-hCG) levels. Triploidy of paternal origin was found in 14 cases (30.4%) and was associated with an increased nuchal translucency, placental molar changes, and a high free β-hCG. Prospective prediction of the parental origin of the triploidy was made in 30 of the 46 cases based on phenotypical ultrasound presentation, and it was correct in all cases. Conclusion: Asymmetrical growth restriction with severe HC/AC discrepancy is pathognomonic of maternal triploidy. Placental molar changes indicate a paternal triploidy. Moreover, triploidy can present with an abnormal first trimester combined test, with serum levels on the extreme end. When available results of maternal serum markers can support the diagnosis of parental origin of the triploidy, an accurate assessment of the parental origin based on prenatal sonographic features is possible, making DNA analysis redundant

Development of placental abnormalities in location and anatomy

Low-lying placentas, placenta previa and abnormally invasive placentas are the most frequently occurring placental abnormalities in location and anatomy. These conditions can have serious consequences for mother and fetus mainly due to excessive blood loss before, during or after delivery. The incidence of such abnormalities is increasing, but treatment options and preventive strategies are limited. Therefore, it is crucial to understand the etiology of placental abnormalities in location and anatomy. Placental formation already starts at implantation and therefore disorders during implantation may cause these abnormalities. Understanding of the normal placental structure and development is essential to comprehend the etiology of placental abnormalities in location and anatomy, to diagnose the affected women and to guide future research for treatment and preventive strategies. We reviewed the literature on the structure and development of the normal placenta and the placental development resulting in low-lying placentas, placenta previa and abnormally invasive placentas

Development of placental abnormalities in location and anatomy

Low-lying placentas, placenta previa and abnormally invasive placentas are the most frequently occurring placental abnormalities in location and anatomy. These conditions can have serious consequences for mother and fetus mainly due to excessive blood loss before, during or after delivery. The incidence of such abnormalities is increasing, but treatment options and preventive strategies are limited. Therefore, it is crucial to understand the etiology of placental abnormalities in location and anatomy. Placental formation already starts at implantation and therefore disorders during implantation may cause these abnormalities. Understanding of the normal placental structure and development is essential to comprehend the etiology of placental abnormalities in location and anatomy, to diagnose the affected women and to guide future research for treatment and preventive strategies. We reviewed the literature on the structure and development of the normal placenta and the placental development resulting in low-lying placentas, placenta previa and abnormally invasive placentas

The influence of the introduction of a national prenatal screening program on late termination of pregnancy, a retrospective cohort study

Objective: To assess the influence of a national prenatal screening program on category 1 (lethal anomalies) late terminations of pregnancy (LTOP). Methods: In this population-based retrospective cohort study, we included all category 1 LTOPs from 2004 to 2015 in the Netherlands. The number of LTOPs before and after the introduction of the program was compared as well as the diagnostic process and factors contributing to LTOP. Results: In total, 97 LTOPs were reported. After the introduction of the program, the number of LTOPs decreased from 17 per year to 5 per year on average. The number of cases in which the diagnostic process started with obstetric indications decreased from 55% to 17% (p &lt; 0.01) and the number of cases detected by routine screening increased from 11% to 52% (p &lt; 0.01). Four factors still contributed to LTOP after the introduction of the screening program: diagnostic or parental delay (40%), absence of screening (24%), false negative results of prior screening (14%) and late onset of disease (12%). Conclusion: The number of LTOPs decreased after the introduction of the screening program. At present, the diagnostic process is mostly screening driven. Parental- and diagnostic delay is still an important factor that contributes to LTOP.</p

Differentially Expressed Genes in the Pre-Eclamptic Placenta: A Systematic Review and Meta-Analysis

<div><p>Objective</p><p>To systematically review the literature on human gene expression data of placental tissue in pre-eclampsia and to characterize a meta-signature of differentially expressed genes in order to identify novel putative diagnostic markers.</p><p>Data Sources</p><p>Medline through 11 February 2011 using MeSH terms and keywords related to placenta, gene expression and gene expression arrays; GEO database using the term “placent*”; and reference lists of eligible primary studies, without constraints.</p><p>Methods</p><p>From 1068 studies retrieved from the search, we included original publications that had performed gene expression array analyses of placental tissue in the third trimester and that reported on differentially expressed genes in pre-eclampsia versus normotensive controls. Two reviewers independently identified eligible studies, extracted descriptive and gene expression data and assessed study quality. Using a vote-counting method based on a comparative meta-profiling algorithm, we determined a meta-signature that characterizes the significant intersection of differentially expressed genes from the collection of independent gene signatures.</p><p>Results</p><p>We identified 33 eligible gene expression array studies of placental tissue in the 3^rd trimester comprising 30 datasets on mRNA expression and 4 datasets on microRNA expression. The pre-eclamptic placental meta-signature consisted of 40 annotated gene transcripts and 17 microRNAs. At least half of the mRNA transcripts encode a protein that is secreted from the cell and could potentially serve as a biomarker.</p><p>Conclusions</p><p>In addition to well-known and validated genes, we identified 14 transcripts not reported previously in relation to pre-eclampsia of which the majority is also expressed in the 1^st trimester placenta, and three encode a secreted protein.</p></div