Metaanalyses of randomized controlled trials have reported contradictory results about the effect of aspirin in the prevention of preeclampsia, both in terms of the gestational age at the onset of ...treatment and the dose of the drug. The controversy may be resolved by a metaanalysis that includes several recently published trials and particularly the large Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention trial and by examination of whether there is a difference of the effect of aspirin on preterm vs term preeclampsia.
We performed a systematic review and metaanalysis that evaluated the prophylactic effect of aspirin during pregnancy.
We completed a literature search through PubMed, Cinhal, Embase, Web of Science, and Cochrane library from 1985 to June 2017. Relative risks with random effect were calculated with their 95% confidence intervals.
Sixteen trials that included 18,907 participants provided data for preterm and term preeclampsia. Eight of the included studies were evaluated as being of good quality, and the other 8 studies were deemed to be of poor or uncertain quality. There was high heterogeneity within studies (I2 >50%) for preterm and term preeclampsia, but no heterogeneity was found in the subgroup of preterm preeclampsia when the onset of treatment was ≤16 weeks of gestation and the daily dose of aspirin was ≥100 mg (I2=0%). Administration of aspirin was associated with reduction in the risk of preterm preeclampsia (relative risk, 0.62; 95% confidence interval, 0.45–0.87), but there was no significant effect on term preeclampsia (relative risk, 0.92; 95% confidence interval, 0.70–1.21). The reduction in preterm preeclampsia was confined to the subgroup in which aspirin was initiated at ≤16 weeks of gestation and at a daily dose of ≥100 mg (relative risk, 0.33; 95% confidence interval, 0.19–0.57). This effect was also observed in the high-quality studies. The reduction in preterm preeclampsia that was observed in the largest trial (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention; n=1620; relative risk, 0.38; 95% confidence interval, 0.20–0.72) was similar to that in the 5 smaller trials in which aspirin was initiated at ≤16 weeks of gestation and at a daily dose of ≥100 mg (n=639; relative risk, 0.22; 95% confidence interval, 0.07–0.66).
Aspirin reduces the risk of preterm preeclampsia, but not term preeclampsia, and only when it is initiated at ≤16 weeks of gestation and at a daily dose of ≥100 mg.
The established method of the assessment of the risk for development of preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such ...factors, the patient is classified as high risk and in their absence as low risk. Although this approach is simple to perform, it has poor performance of the prediction of preeclampsia and does not provide patient-specific risks. This review describes a new approach that allows the estimation of patient-specific risks of delivery with preeclampsia before any specified gestational age by maternal demographic characteristics and medical history with biomarkers obtained either individually or in combination at any stage in pregnancy. In the competing risks approach, every woman has a personalized distribution of gestational age at delivery with preeclampsia; whether she experiences preeclampsia or not before a specified gestational age depends on competition between delivery before or after the development of preeclampsia. The personalized distribution comes from the application of Bayes theorem to combine a previous distribution, which is determined from maternal factors, with likelihoods from biomarkers. As new data become available, what were posterior probabilities take the role as the previous probability, and data collected at different stages are combined by repeating the application of Bayes theorem to form a new posterior at each stage, which allows for dynamic prediction of preeclampsia. The competing risk model can be used for precision medicine and risk stratification at different stages of pregnancy. In the first trimester, the model has been applied to identify a high-risk group that would benefit from preventative therapeutic interventions. In the second trimester, the model has been used to stratify the population into high-, intermediate-, and low-risk groups in need of different intensities of subsequent monitoring, thereby minimizing unexpected adverse perinatal events. The competing risks model can also be used in surveillance of women presenting to specialist clinics with signs or symptoms of hypertensive disorders; combination of maternal factors and biomarkers provide patient-specific risks for preeclampsia that lead to personalized stratification of the intensity of monitoring, with risks updated on each visit on the basis of biomarker measurements.
Background Preeclampsia affects approximately 3% of all pregnancies and is a major cause of maternal and perinatal morbidity and death. In the last decade, extensive research has been devoted to ...early screening for preeclampsia with the aim of reducing the prevalence of the disease through pharmacologic intervention in the high-risk group starting from the first trimester of pregnancy. Objective The purpose of this study was to develop a model for preeclampsia based on maternal demographic characteristics and medical history (maternal factors) and biomarkers. Study Design The data for this study were derived from prospective screening for adverse obstetric outcomes in women who attended for their routine first hospital visit at 11-13 weeks gestation in 2 maternity hospitals in England. We screened 35,948 singleton pregnancies that included 1058 pregnancies (2.9%) that experienced preeclampsia. Bayes theorem was used to combine the a priori risk from maternal factors with various combinations of uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein-A, and placental growth factor multiple of the median values. Five-fold cross validation was used to assess the performance of screening for preeclampsia that delivered at <37 weeks gestation (preterm-preeclampsia) and ≥37 weeks gestation (term-preeclampsia) by models that combined maternal factors with individual biomarkers and their combination with screening by maternal factors alone. Results In pregnancies that experienced preeclampsia, the values of uterine artery pulsatility index and mean arterial pressure were increased, and the values of serum pregnancy-associated plasma protein-A and placental growth factor were decreased. For all biomarkers, the deviation from normal was greater for early than late preeclampsia; therefore, the performance of screening was related inversely to the gestational age at which delivery became necessary for maternal and/or fetal indications. Combined screening by maternal factors, uterine artery pulsatility index, mean arterial pressure, and placental growth factor predicted 75% (95% confidence interval, 70-80%) of preterm-preeclampsia and 47% (95% confidence interval, 44-51%) of term-preeclampsia, at a false-positive rate of 10%; inclusion of pregnancy-associated plasma protein-A did not improve the performance of screening. Such detection rates are superior to the respective values of 49% (95% confidence interval, 43-55%) and 38% (34-41%) that were achieved by screening with maternal factors alone. Conclusion Combination of maternal factors and biomarkers provides effective first-trimester screening for preterm-preeclampsia.
Objective The purpose of this study was to develop a model for preeclampsia based on maternal demographic characteristics and medical history. Study Design This was a screening study of 120,492 ...singleton pregnancies at 11-13 weeks' gestation, including 2704 pregnancies (2.2%) that experienced preeclampsia. A survival-time model for the gestational age at delivery with preeclampsia was developed from variables of maternal characteristics and history. This approach assumes that, if the pregnancy was to continue indefinitely, all women would experience preeclampsia and that whether they do so or not before a specified gestational age depends on competition between delivery before or after development of preeclampsia. A 5-fold cross validation study was conducted to compare the performance of the new model with the National Institute for Health and Clinical Excellence (NICE) guidelines. Results In the new model, increased risk for preeclampsia, with a consequent shift in the Gaussian distribution of the gestational age at delivery with preeclampsia to the left, is provided by advancing maternal age, increasing weight, Afro-Caribbean and South Asian racial origin, medical history of chronic hypertension, diabetes mellitus and systemic lupus erythematosus or antiphospholipid syndrome, family history and personal history of preeclampsia, and conception by in vitro fertilization. The risk for preeclampsia decreases with increasing maternal height and in parous women with no previous preeclampsia; in the latter, the protective effect, which is related inversely to the interpregnancy interval, persists beyond 15 years. At a screen-positive rate of 11%, as defined by NICE, the new model predicted 40%, 48%, and 54% of cases of total preeclampsia and preeclampsia requiring delivery at <37 and <34 weeks’ gestation, respectively, which were significantly higher than the respective values of 35%, 40%, and 44% achieved by application of NICE guidelines. Conclusion A new model that is based on maternal characteristics and medical history has been developed for the estimation of patient-specific risks for preeclampsia. Such estimation of the a priori risk for preeclampsia is an essential first step in the use of Bayes theorem to combine maternal factors with biomarkers for the continuing development of more effective methods of screening for the disease.
Impaired placentation in the first 16 weeks of pregnancy is associated with increased risk of subsequent development of preeclampsia, birth of small-for-gestational-age neonates, and placental ...abruption. Previous studies reported that prophylactic use of aspirin reduces the risk of preeclampsia and small-for-gestational-age neonates with no significant effect on placental abruption. However, meta-analyses of randomized controlled trials that examined the effect of aspirin in relation to gestational age at onset of therapy and dosage of the drug reported that significant reduction in the risk of preeclampsia and small-for-gestational-age neonates is achieved only if the onset of treatment is at ≤16 weeks of gestation and the daily dosage of the drug is ≥100 mg.
We aimed to estimate the effect of aspirin on the risk of placental abruption or antepartum hemorrhage in relation to gestational age at onset of therapy and the dosage of the drug.
To perform a systematic review and meta-analysis of randomized controlled trials that evaluated the prophylactic effect of aspirin during pregnancy, we used PubMed, Cinhal, Embase, Web of Science and Cochrane library from 1985 to September 2017. Relative risks of placental abruption or antepartum hemorrhage with their 95% confidence intervals were calculated with the use of random effect models. Analyses were stratified according to daily dose of aspirin (<100 and ≥100 mg) and the gestational age at the onset of therapy (≤16 and >16 weeks of gestation) and compared with the use of subgroup difference analysis.
The entry criteria were fulfilled by 20 studies on a combined total of 12,585 participants. Aspirin at a dose of <100 mg per day had no impact on the risk of placental abruption or antepartum hemorrhage, irrespective of whether it was initiated at ≤16 weeks of gestation (relative risk, 1.11; 95% confidence interval, 0.52–2.36) or at >16 weeks of gestation (relative risk, 1.32; 95% confidence interval, 0.73–2.39). At ≥100 mg per day, aspirin was not associated with a significant change on the risk of placental abruption or antepartum hemorrhage, whether the treatment was initiated at ≤16 weeks of gestation (relative risk, 0.62, 95% confidence interval, 0.31–1.26), or at >16 weeks of gestation (relative risk, 2.08; 95% confidence interval, 0.86–5.06), but the difference between the subgroups was significant (P=.04).
Aspirin at a daily dose of ≥100 mg for prevention of preeclampsia that is initiated at ≤16 weeks of gestation, rather than >16 weeks, may decrease the risk of placental abruption or antepartum hemorrhage.
The current approach to prenatal care, which involves visits at 16, 24, 28, 30, 32, 34 and 36 weeks and then weekly until delivery, was established 80 years ago. The high concentration of visits in ...the third trimester implies, firstly, that most complications occur at this late stage of pregnancy and, secondly, that most adverse outcomes are unpredictable during the first or even second trimester. This review presents evidence that many pregnancy complications can now be predicted at an integrated first hospital visit at 11-13 weeks by combining data from maternal characteristics and history with findings of biophysical and biochemical tests. It is therefore proposed that the traditional pyramid of care should be inverted with the main emphasis placed in the first rather than third trimester of pregnancy.
Prevention of preeclampsia with aspirin Rolnik, Daniel L.; Nicolaides, Kypros H.; Poon, Liona C.
American journal of obstetrics and gynecology,
February 2022, 2022-02-00, 20220201, Letnik:
226, Številka:
2
Journal Article
Recenzirano
Preeclampsia is defined as hypertension arising after 20 weeks of gestational age with proteinuria or other signs of end-organ damage and is an important cause of maternal and perinatal morbidity and ...mortality, particularly when of early onset. Although a significant amount of research has been dedicated in identifying preventive measures for preeclampsia, the incidence of the condition has been relatively unchanged in the last decades. This could be attributed to the fact that the underlying pathophysiology of preeclampsia is not entirely understood. There is increasing evidence suggesting that suboptimal trophoblastic invasion leads to an imbalance of angiogenic and antiangiogenic proteins, ultimately causing widespread inflammation and endothelial damage, increased platelet aggregation, and thrombotic events with placental infarcts. Aspirin at doses below 300 mg selectively and irreversibly inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane and inhibiting inflammation and platelet aggregation. Such an effect has led to the hypothesis that aspirin could be useful for preventing preeclampsia. The first possible link between the use of aspirin and the prevention of preeclampsia was suggested by a case report published in 1978, followed by the first randomized controlled trial published in 1985. Since then, numerous randomized trials have been published, reporting the safety of the use of aspirin in pregnancy and the inconsistent effects of aspirin on the rates of preeclampsia. These inconsistencies, however, can be largely explained by a high degree of heterogeneity regarding the selection of trial participants, baseline risk of the included women, dosage of aspirin, gestational age of prophylaxis initiation, and preeclampsia definition. An individual patient data meta-analysis has indicated a modest 10% reduction in preeclampsia rates with the use of aspirin, but later meta-analyses of aggregate data have revealed a dose-response effect of aspirin on preeclampsia rates, which is maximized when the medication is initiated before 16 weeks of gestational age. Recently, the Aspirin for Evidence-Based Preeclampsia Prevention trial has revealed that aspirin at a daily dosage of 150 mg, initiated before 16 weeks of gestational age, and given at night to a high-risk population, identified by a combined first trimester screening test, reduces the incidence of preterm preeclampsia by 62%. A secondary analysis of the Aspirin for Evidence-Based Preeclampsia Prevention trial data also indicated a reduction in the length of stay in the neonatal intensive care unit by 68% compared with placebo, mainly because of a reduction in births before 32 weeks of gestational age with preeclampsia. The beneficial effect of aspirin has been found to be similar in subgroups according to different maternal characteristics, except for the presence of chronic hypertension, where no beneficial effect is evident. In addition, the effect size of aspirin has been found to be more pronounced in women with good compliance to treatment. In general, randomized trials are underpowered to investigate the treatment effect of aspirin on the rates of other placental-associated adverse outcomes such as fetal growth restriction and stillbirth. This article summarizes the evidence around aspirin for the prevention of preeclampsia and its complications.
Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated ...congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking.
In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women.
The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval CI, 1.22 to 6.11; two-sided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09).
In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.).
Randomized controlled trials that have assessed the efficacy of cervical pessary to prevent preterm birth in asymptomatic high-risk women have reported conflicting results.
To evaluate the efficacy ...and safety of cervical pessary to prevent preterm birth and adverse perinatal outcomes in asymptomatic high-risk women.
MEDLINE, EMBASE, POPLINE, CINAHL, and LILACS (from their inception to October 31, 2019), Cochrane databases, Google Scholar, bibliographies, and conference proceedings.
Randomized controlled trials that compared cervical pessary with standard care (no pessary) or alternative interventions in asymptomatic women at high risk for preterm birth.
The systematic review was conducted according to the Cochrane Handbook guidelines. The primary outcome was spontaneous preterm birth <34 weeks of gestation. Secondary outcomes included adverse pregnancy, maternal, and perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. Quality of evidence was assessed using the GRADE methodology.
Twelve studies (4687 women and 7167 fetuses/infants) met the inclusion criteria: 8 evaluated pessary vs no pessary in women with a short cervix, 2 assessed pessary vs no pessary in unselected multiple gestations, and 2 compared pessary vs vaginal progesterone in women with a short cervix. There were no significant differences between the pessary and no pessary groups in the risk of spontaneous preterm birth <34 weeks of gestation among singleton gestations with a cervical length ≤25 mm (relative risk, 0.80; 95% confidence interval, 0.43−1.49; 6 trials, 1982 women; low-quality evidence), unselected twin gestations (relative risk, 1.05; 95% confidence interval, 0.79−1.41; 1 trial, 1177 women; moderate-quality evidence), twin gestations with a cervical length <38 mm (relative risk, 0.75; 95% confidence interval, 0.41−1.36; 3 trials, 1128 women; low-quality evidence), and twin gestations with a cervical length ≤25 mm (relative risk; 0.72, 95% confidence interval, 0.25−2.06; 2 trials, 348 women; low-quality evidence). Overall, no significant differences were observed between the pessary and no pessary groups in preterm birth <37, <32, and <28 weeks of gestation, and most adverse pregnancy, maternal, and perinatal outcomes (low- to moderate-quality evidence for most outcomes). There were no significant differences in the risk of spontaneous preterm birth <34 weeks of gestation between pessary and vaginal progesterone in singleton gestations with a cervical length ≤25 mm (relative risk, 0.99; 95% confidence interval, 0.54−1.83; 1 trial, 246 women; low-quality evidence) and twin gestations with a cervical length <38 mm (relative risk, 0.73; 95% confidence interval, 0.46−1.18; 1 trial, 297 women; very low-quality evidence). Vaginal discharge was significantly more frequent in the pessary group than in the no pessary and vaginal progesterone groups (relative risks, ∼2.20; high-quality evidence).
Current evidence does not support the use of cervical pessary to prevent preterm birth or to improve perinatal outcomes in singleton or twin gestations with a short cervix and in unselected twin gestations.
PDF
