Recurrent Placenta-mediated Pregnancy Complications Research Articles

The risk of cesarean delivery after labor induction among women with prior pregnancy complications: a subgroup analysis of the AFFIRM study

BackgroundTo determine the risk of cesarean delivery after labor induction among patients with prior placenta-mediated pregnancy complications (pre-eclampsia, late pregnancy loss, placental abruption or intrauterine growth restriction).MethodsThe AFFIRM database includes patient level data from 9 randomized controlled trials that evaluated the role of LMWH versus no LMWH during pregnancy to prevent recurrent placenta-mediated pregnancy complications. The primary outcome of this sub-study was the proportion of women who had an unplanned cesarean delivery after induction of labor compared to after spontaneous labor.ResultsThere were 512 patients from 7 randomized trials included in our sub-study. There was no difference in the risk of cesarean delivery between women with labor induction (21/148, 14.2%) and spontaneous labor (79/364, 21.7%) (odds ratio (OR) 0.60, 95% CI, 0.35–1.01; p = 0.052). Among 274 women who used LMWH prophylaxis during pregnancy, the risk of cesarean delivery was lower among those that underwent labor induction (9.8%) compared to spontaneous labor (22.4%) (OR 0.38, 95% CI, 0.17–0.84; p = 0.01).ConclusionsThe risk of cesarean delivery is not increased after labor induction among a higher risk patient population with prior pregnancy complications. Our results suggest that women who receive LMWH during pregnancy might benefit from labor induction.

Comparison of 2 approaches in management of pregnant women with inherited trombophilias: Prospective analytical cohort study.

Previous adverse pregnancy outcomes (APO) in women with hereditary thrombophilia have emerged as new indications for prophylactic use of low-molecular-weight heparin (LMWH) during pregnancy. Recent meta-analysis conducted to establish if LMWH may prevent recurrent placenta-mediated pregnancy complications point to important therapeutic effect but these findings are absolutely not universal. Furthermore, previous studies regarding LMWH prophylaxis for APO in women with inherited thrombophilia were performed in high risk patients with previous adverse health outcomes in medical, family and/or obstetric history. Therefore, the aim of this study was to investigate the effects of LMWH prophylaxis on pregnancy outcomes in women with inherited thrombophilias regardless of the presence of previous adverse health outcomes in medical, family, and obstetric history.Prospective analytical cohort study included all referred women with inherited thrombophilia between 11 and 15 weeks of gestation and followed-up to delivery. Patients were allocated in group with LWMH prophylaxis (study group) and control group without LWMH prophylaxis. The groups were compared for laboratory parameters and Doppler flows of umbilical artery at 28th to 30th, 32nd to 34th and 36th to 38th gestational weeks (gw), and for obstetric and perinatal outcomes.The study group included 221 women and control group included 137 women. Mean resistance index of the umbilical artery Ri in 28 to 30, 32 to 34, and 36 to 38 gw were significantly higher in the control group compared to study group (0.71 ± 0.02 vs 0.69 ± 0.02; 0.67 ± 0.03 vs 0.64 ± 0.02; and 0.67 ± 0.05 vs 0.54 ± 0.08, respectively). Intrauterine fetal death (IUFD) and miscarriages were statistically significantly more frequent in control group compared to the patients in study (P < .001). The frequencies of fetal growth restriction (FGR) and APO were significantly higher in the control group compared to the study group (P = .008 and P < .001, respectively). In a multivariate regression model with APO as a dependent variable, only Ri was detected as a significant protective factor for APO, after adjusting for age and LMWH prophylaxis (P < .001).We have demonstrated better perinatal outcomes in women with LMWH prophylaxis for APO compared to untreated women.

Can certain factors for recurrence of placenta-mediated pregnancy complications be identified after an initial small-for-gestational-age birth?

Introduction: After a small-for-gestational-age (SGA) birth, recurrence of placenta-mediated pregnancy complications (PMPCs) is a cause for anxiety when contemplating another pregnancy. We sought to identify factors potentially associated with this recurrence.Material and methods: This retrospective single-center observational study was conducted in a tertiary maternity unit between 1 January 2010 and 31 December 2017. We included all women having experienced a non-syndromic SGA birth and who were subsequently monitored for at least one other pregnancy in our institution. PMPCs were defined as recurrent SGA births, three consecutive first-trimester miscarriages, or preeclampsia.Results: Ninety-four women were included over a 7-year study period. Recurrent PMPCs were recorded in 30 (32%) cases, of which 29 featured recurrent SGA births. None of the following characteristics were significantly associated with recurrence: presence of preeclampsia during the initial pregnancy (six [20%] versus 25 [39%] cases in the recurrent PMPCs and non-recurrent PMPCs groups, respectively; p = .11), results of the histopathologic placental examination or thrombophilia screen, or implemented treatment during subsequent pregnancies.Conclusions: PMPCs recur frequently. No risk factor for recurrence was identified in our study. Results of etiologic assessments and treatments implemented after an initial SGA birth should therefore not modify level of clinical and ultrasound monitoring provided during subsequent pregnancies.Rationale: Recurrence of placenta-mediated pregnancy complications is a cause for anxiety when contemplating another pregnancy. We did not identify any risk factor after an initial small-for-gestational-age birth in our study; surveillance should therefore not be modified by the etiologic assessments’ results.

441. LMW heparin and recurrent placenta-mediated pregnancy complications: An individual participant data meta-analysis

Placenta-mediated pregnancy complications, including pre-eclampsia, placental abruption, birth of a small-for-gestational age infant and late pregnancy loss, are common and cause significant morbidity and mortality. The use of antepartum low-molecular-weight heparin (LMWH) prophylaxis to prevent recurrent placenta-mediated pregnancy complications became common practice despite limited and conflicting evidence supporting its use. Unfortunately, differences in the study design of individual randomized controlled trials have limited comparison across trials. In this talk we will review data from an individual patient data meta-analysis that challenges the role of LMWH in preventing recurrent placenta-mediated pregnancy complications.

Aspirin or heparin or both in the treatment of recurrent spontaneous abortion in women with antiphospholipid antibody syndrome: a meta-analysis of randomized controlled trials

Objective: This study was designed to evaluate the efficacy of aspirin or heparin or both in the treatment for recurrent spontaneous abortion (RSA) in women with antiphospholipid antibody syndrome (APS).Methods: Systematic searches for randomized clinical trials (RCTs) evaluating on live birth and preterm delivery, preeclampsia, intrauterine growth restriction, gestational diabetes, bleeding of RSA with APS patients receiving aspirin, and heparin therapy were carried out, from PubMed, EMBASE, ScienceDirect, and CNKI. Related data were extracted from eligible studies and then subjected to Reviewer Manage 5.3 for analysis. Relative risk (RR) and its 95% confidence interval were calculated.Results: Nineteen publications with randomized controlled trials were selected for this study, which included a total of 1251 pregnant patients with diagnosis of RSA with APS. With respect to live birth, it was remarkably improved in aspirin plus heparin or heparin alone group [RR =1.23, 95% CI (1.12–1.36), p < .0001; RR = 1.18, 95% CI (1.03–1.35), p = .02]; aspirin alone group, however, there was no statistically significant difference compare to placebo [RR = 0.97, 95% CI (0.80–1.16), p = .71]. Meanwhile, aspirin plus heparin therapy did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications including preterm birth, intrauterine growth retardation (IUGR), gestational diabetes, and minor bleeding. A beneficial therapeutic effect of heparin alone therapy was found on preventing preterm birth and low-dose aspirin plus heparin therapy was significant reduce the risk of preeclampsia.Conclusion: An improvement of pregnancy outcomes in women with RSA and APS can be achieved by treatment strategies combining low-dose aspirin plus heparin or heparin alone. Aspirin alone, by contrast, seemed inferior to other treatments in achieving more live birth.

Low–molecular-weight Heparin and Recurrent Placenta-mediated Pregnancy Complications: A Meta-Analysis of Individual Patient Data From Randomized Controlled Trials

(Lancet. 2016;388:2629–2641) Placenta-mediated pregnancy complications include preeclampsia, birth of a small for gestational age (SGA) neonate, placental abruption, and late pregnancy loss. They are significant contributors to maternal and neonatal morbidity and mortality. Patients experiencing these complications are also at risk of placenta-mediated complications occurring in subsequent pregnancies. Effective preventive measures for these complications are generally lacking. The current investigators had previously published a study-level meta-analysis that indicated low–molecular-weight heparin (LMWH) could reduce the risk of recurrence. However, there was significant heterogeneity in that study so they decided to perform an individual patient data meta-analysis to evaluate the efficacy of LMWH to prevent recurrent placenta-mediated complications in subsequent pregnancies.

Low-Molecular-Weight Heparin and Recurrent Placenta-Mediated Pregnancy Complications: A Meta-analysis of Individual Patient Data From Randomised Controlled Trials

Placenta-mediated pregnancy complications include pre-eclampsia, birth of a small-for-gestational-age neonate, placental abruption, or late pregnancy loss and lead to maternal and fetal or neonatal morbidity and mortality. These complications have a high risk of recurring in subsequent pregnancies, and effective preventive measures are lacking. Findings from some randomized controlled trials suggest that low-molecular-weight heparin (LMWH) can be used to prevent recurrent placentamediated pregnancy complications, but these findings have not been universal. An individual patient data meta-analysis was done to evaluate the efficacy of LMWH to prevent recurrent placentamediated complications in subsequent pregnancies. The primary outcome was a composite of 4 pregnancy complications: early-onset or severe preeclampsia, birth of a small-for-gestational-age neonate (birth weight less than the fifth percentile), placental abruption, and late pregnancy loss. The data set included a total of 963 eligiblewomen from 8 randomized published trials. The primary outcome analysis showed that LMWH did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (LMWH 62/444 [14%] vs no LMWH 95/443 [22%]; absolute difference, 8% [95% confidence interval, 17.3-1.4; P = 0.09]; relative risk, 0.64 [95% confidence interval, 0.36-1.11; P = 0.11]). Significant heterogeneity was noted between single-center and multicenter trials for the primary composite outcomes and also in the subgroup analyses. Low-molecular-weight heparin was found to be beneficial in women with previous placental abruption in both single-center and multicenter trials but not in any other subgroups of previous complications. No serious adverse reaction to LMWHwas observed. Inclusion of individual patient data set enabled a robust exploration of clinical, methodological, and statistical heterogeneity. In conclusion, this individual patient data meta-analysis showed that LMWH did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications in women with previous complications

Anticoagulants to prevent recurrent placenta-mediated pregnancy complications: Is it time to put the needles away?

Placenta-mediated pregnancy complications, such as pre-eclampsia, placental abruption, birth of a small-for-gestational age infant and late pregnancy loss, are common and carry significant morbidity and mortality. The etiology of placenta-mediated pregnancy complications is likely multifactorial and may include abnormal coagulation activation of the maternal-fetal interface. The use of antepartum low-molecular-weight heparin (LMWH) prophylaxis to prevent recurrent placenta-mediated pregnancy complications has become common practice despite limited and conflicting evidence to support its use. This paper reviews the evidence, including recently published data from an individual patient level meta-analysis, which challenges the role of LMWH in preventing recurrent placenta-mediated pregnancy complications. Incorporating this recent evidence, we recommend against the use of LMWH to prevent recurrent placenta-mediated pregnancy complications in women with and without inherited thrombophilia.

Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials

Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. Canadian Institutes of Health Research.

Adjusting enoxaparin dosage according to anti-FXa levels and pregnancy outcome in thrombophilic women

Women with thrombophilias and previous placenta-mediated pregnancy complications (PMPC) have an increased risk of both recurrent PMPC and venous thromboembolism (VTE) during subsequent pregnancies. We aimed to examine whether enoxaparin dose adjusted according to anti-factor Xa levels compared to a fixed dose would reduce the risk of PMPC in subsequent pregnancies. In a randomised trial, conducted at a single teaching hospital, pregnant women with thrombophilia and previous PMPC were enrolled in a 1:1 ratio to either a fixed dose of 40 mg daily enoxaparin or adjusted dose according to anti-factor Xa plasma levels. The primary outcome was a composite that included any of the following: pregnancy loss after enrollment, pre-eclampsia, birthweight <10th percentile, placental abruption, or VTE. Overall, 144 women were needed to detect a decrease of 20 % in the incidence of the composite outcome among the adjusted dose group. Between 2009 and 2015, 144 women consented; four in the fixed-dose group were excluded. Overall, 66 and 74 in the fixed- and adjusted-dose groups, respectively, were included. Demographic and obstetric characteristics were comparable. Composite outcome occurred in 12 (18.2 %) and 20 (27.0 %) women in the fixed- and adjusted-dose groups, respectively (p=0.24). Gestational age at delivery, preterm births, and birthweights were similar between the two groups. In conclusion, dose of enoxaparin adjusted according to anti-factor Xa levels compared to fixed dose, does not reduce the risk of PMPC recurrence in thrombophilic women.

Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications: protocol for a systematic review and individual patient data meta-analysis (AFFIRM).

BackgroundPlacenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications.Methods/DesignWe conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy.DiscussionThe goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin.Systematic review registrationPROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249

Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications

A 35-year-old woman with recurrent severe placenta-mediated pregnancy complications in her 2 pregnancies asks: Will low-molecular-weight heparin help prevent recurrent placenta-mediated pregnancy complications in my next pregnancy? We performed a meta-analysis of randomized controlled trials (RCTs) comparing low-molecular-weight heparin (LMWH) vs no LMWH for the prevention of recurrent placenta-mediated pregnancy complications. We identified six RCTs that included a total of 848 pregnant women with prior placenta-mediated pregnancy complications. The primary outcome was a composite of pre-eclampsia (PE), birth of a small-for-gestational-age (SGA) newborn (<10th percentile), placental abruption, or pregnancy loss >20 weeks. Overall, 67 (18.7%) of 358 of women being given prophylactic LMWH had recurrent severe placenta-mediated pregnancy complications compared with 127 (42.9%) of 296 women with no LMWH (relative risk reduction, 0.52; 95% CI, 0.32 to 0.86; P = .01; I(2), 69%, indicating moderate heterogeneity). We identified similar relative risk reductions with LMWH for individual outcomes, including any PE, severe PE, SGA <10th percentile, SGA <5th percentile, preterm delivery <37 weeks, and preterm delivery <34 weeks with minimal heterogeneity. LMWH may be a promising therapy for recurrent, especially severe, placenta-mediated pregnancy complications, but further research is required.

An update on thrombophilia and placenta mediated pregnancy complications: What should we tell our patients?

The placenta mediated pregnancy complications, including pre-eclampsia, birth of a small for gestational age child, placental abruption or late pregnancy loss, are common and often devastating pregnancy complications leading to important maternal/fetal/neonatal morbidity and mortality. In this narrative review I examine two common questions related to women with prior placenta mediated pregnancy complications. Do thrombophilias cause placenta mediated pregnancy complications? Does low molecular weight heparin prevent recurrent placenta mediated pregnancy complications?