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

Rodger, M.; Gris, J.-C.; Vries, J.I.P. de; Martinelli, Ida; Rey, É.; Schleußner, E; Kaaja, Risto; Langlois, Nicole; Ramsay, Timothy; Mallick, Ranjeeta; Bates, Shannon M.; Abheiden, Carolien N H; Perna, Annalisa; Petroff, David; Jong, Paulien de; Hoorn, Marion E. van; Bezemer, P.D.; Mayhew, Alain

doi:10.1097/01.aoa.0000521245.79372.fb

Cited by 3 publications

(5 citation statements)

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“…The role of heparin to prevent SGA Consistent with an earlier metaanalysis, 44 the Canadian guideline recommends that heparin should be offered in selected women. The publication of an individual patient data meta-analysis, 45 along with findings from the Enoxaparin for the Prevention of Preeclampsia and Intrauterine Growth Restriction trial, 46 have demonstrated that enoxaparin is not effective in preventing FGR in women with previous severe or early-onset FGR, or in those with thrombophilia, and can therefore not be recommended for this purpose.…”

Section: Expert Reviewsmentioning

confidence: 75%

Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy

McCowan

Figueras

Anderson

2018

American Journal of Obstetrics and Gynecology

344

312

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Small for gestational age is usually defined as an infant with a birthweight <10th centile for a population or customized standard. Fetal growth restriction refers to a fetus that has failed to reach its biological growth potential because of placental dysfunction. Small-for-gestational-age babies make up 28-45% of nonanomalous stillbirths, and have a higher chance of neurodevelopmental delay, childhood and adult obesity, and metabolic disease. The majority of small-for-gestational-age babies are not recognized before birth. Improved identification, accompanied by surveillance and timely delivery, is associated with reduction in small-for-gestational-age stillbirths. Internationally and regionally, detection of small for gestational age and management of fetal growth problems vary considerably. The aim of this review is to: summarize areas of consensus and controversy between recently published national guidelines on small for gestational age or fetal growth restriction; highlight any recent evidence that should be incorporated into existing guidelines; and identify future research priorities in this field. A search of MEDLINE, Google, and the International Guideline Library identified 6 national guidelines on management of pregnancies complicated by fetal growth restriction/small for gestational age published from 2010 onwards. There is general consensus between guidelines (at least 4 of 6 guidelines in agreement) in early pregnancy risk selection, and use of low-dose aspirin for women with major risk factors for placental insufficiency. All highlight the importance of smoking cessation to prevent small for gestational age. While there is consensus in recommending fundal height measurement in the third trimester, 3 specify the use of a customized growth chart, while 2 recommend McDonald rule. Routine third-trimester scanning is not recommended for small-for-gestational-age screening, while women with major risk factors should have serial scanning in the third trimester. Umbilical artery Doppler studies in suspected small-for-gestational-age pregnancies are universally advised, however there is inconsistency in the recommended frequency for growth scans after diagnosis of small for gestational age/fetal growth restriction (2-4 weekly). In late-onset fetal growth restriction (≥32 weeks) general consensus is to use cerebral Doppler studies to influence surveillance and/or delivery timing. Fetal surveillance methods (most recommend cardiotocography) and recommended timing of delivery vary. There is universal agreement on the use of corticosteroids before birth at <34 weeks, and general consensus on the use of magnesium sulfate for neuroprotection in early-onset fetal growth restriction (<32 weeks). Most guidelines advise using cardiotocography surveillance to plan delivery in fetal growth restriction <32 weeks. The recommended gestation at delivery for fetal growth restriction with absent and reversed end-diastolic velocity varies from 32 to ≥34 weeks and 30 to ≥34 weeks, respectively. Overall, where there is high-q...

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Section: Expert Reviewsmentioning

confidence: 75%

Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy

McCowan

Figueras

Anderson

2018

American Journal of Obstetrics and Gynecology

344

312

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“…The authors concluded that LMWH may be a promising therapy for recurrent, especially severe, placenta-mediated pregnancy complications, but they recommended that further research is required. 26 These trials differed from our study because they used abnormal Doppler indices as a sign that the pregnancy should be terminated in an attempt to deliver the fetus in a viable state before the fetal death in uterus. Our study, however, aimed to identify abnormal blood flow state before it affected the fetus and then provided treatment to prevent stillbirth.…”

Section: Discussionmentioning

confidence: 83%

“…A recent meta-analysis of randomized controlled trials examined the use of LMWH for the prevention of recurrent placenta-mediated pregnancy complications. 26 The authors identified 6 trials that included a total of 848 pregnant women with prior placenta-mediated pregnancy complications. The primary outcome was a composite of preeclampsia, birth of a small-for-gestational-age newborn (<10th percentile), placental abruption, or pregnancy loss >20 weeks.…”

Section: Discussionmentioning

confidence: 99%

Bemiparin as a Prophylaxis After an Unexplained Stillbirth: Open-Label Interventional Prospective Study

Jawad

Alalaf

Ali

et al. 2019

Clin Appl Thromb Hemost

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Stillbirth is a devastating event to the parents, relatives, friends, and families. The role of anticoagulants in the prevention of unexplained stillbirths is uncertain. An open-label interventional prospective cohort study was conducted on 144 women with a history of unexplained stillbirths. The intervention group had a high umbilical artery resistance index (RI) and received bemiparin. The nonintervention group had a normal RI and did not receive any intervention. We measured the adjusted odds ratio (OR) and 95% confidence interval (CI) of the main outcome for these variables using logistic regression analysis. Fresh stillbirth and early neonatal death rates were lower ( P = .005, OR = 11.949 and 95% CI = 2.099-68.014) and newborn weight was higher ( P = .015, OR = 0.048, 95% CI = 0.004-0.549) in the group that received bemiparin. Bemiparin is effective in decreasing the rate of stillbirth in women with a history of previous unexplained stillbirths.

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“…45,48 A study-level meta-analysis of 6 trials (848 women) demonstrated LMWH (included trials used enoxaparin, dalteparin, and nadroparin) was associated with a reduction in a composite outcome (preeclampsia, birthweight <10 th percentile, placental abruption, or pregnancy loss >20 weeks), 18.7% vs 42.9% (relative risk, 0.52, 95% CI, 0.32e0.86), with similar risk reductions for a number of secondary outcomes including SGA <10th percentile and less than the fifth percentile. 53 However, there were high levels of heterogeneity across trials and trials of higher-quality suggested no treatment effect.…”

Section: Sites Of Action Of Interventions Under Investigation To Treamentioning

confidence: 99%

“…Effect of gestational age at initiation of aspirin therapy for prevention of FGR or SGA at birthStudy level meta-analysis53 used FGR as outcome to assess fetal size, defined as birthweight <10th or <5th percentile for gestational age or similar definition. The IPD meta-analysis54 used SGA as outcome to assess fetal size; SGA at birth was as defined by individual trialists, including centile charts and cutoff point used.…”

mentioning

confidence: 99%

The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction

Groom

David

2018

American Journal of Obstetrics and Gynecology

133

101

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Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta-mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4-9.2); use of low-molecular-weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction co...

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

Cited by 3 publications

References 0 publications

Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy

Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy

Bemiparin as a Prophylaxis After an Unexplained Stillbirth: Open-Label Interventional Prospective Study

The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction

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