CoChat
Sign Up
Cited by 170Pregnancy and preeclampsia studiesBirth, Development, and HealthPregnancy and Medication Impact

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

Open access
Groom, Katie M., David, Anna L.·2018·American Journal of Obstetrics and Gynecology
DOI 10.1016/j.ajog.2017.11.565
Open this paper in CoChat — free accountOpen PDF

Abstract

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 consortium. Other targeting approaches include nanoparticles and microRNAs to deliver drugs locally to the uterine arterial endothelium or trophoblast. In vitro and in vivo studies and animal models have demonstrated effects of nitric oxide donors, dietary nitrate, hydrogen sulphide donors, statins, and proton pump inhibitors on maternal blood pressure, uteroplacental resistance indices, and angiogenic/antiangiogenic factors. Data from human pregnancies and, in particular, pregnancies with fetal growth restriction remain very limited. Early research into melatonin, creatine, and N-acetyl cysteine supplementation in pregnancy suggests they may have potential as neuro- and cardioprotective agents in fetal growth restriction.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.ajog.2017.11.565

Cites

135 of 135 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • At present, there is no evidence that therapeutic interventions, including sildenafil, improve placental perfusion and outcome in pregnancies with fetal growth restriction.

    “At present, there is no evidence that therapeutic interventions, including sildenafil to augment uteroplacental perfusion through vasodilation, improve placental perfusion and outcome in pregnancies with FGR.75,79”

    From Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction (2020) · cites this paper as [75]

    The Implications for practice section (page unavailable) says there are no proven treatments that improve fetal growth or outcome after FGR is diagnosed. But the clinical-studies discussion (page unavailable) reports reduced umbilical artery resistance after a single sildenafil dose in FGR pregnancies, evidence of an effect on fetoplacental circulation. Thus the claim captures the lack of a proven outcome benefit but overstates the absence of evidence for a perfusion-related effect. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Low-molecular-weight heparin has not been shown to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women.

    “Furthermore, the use of low-molecularweight heparin has not been shown to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women.75,77,78”

    From Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction (2020) · cites this paper as [75]

  • The finding of low-dose aspirin benefit was not confirmed in the ASPRE trial, which was primarily designed for preterm preeclampsia prevention.

    “However, this finding was not confirmed in the Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial, which was primarily designed for preterm preeclampsia prevention.74,75”

    From Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction (2020) · cites this paper as [75]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. [3]3. Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu 1972;1: 177-91.
  2. [81]81. Ganzevoort W, Alfirevic Z, von Dadelszen P, et al. STRIDER (Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Re- striction)-a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. Syst Rev 2014;3:23.
  3. [100]100. ajog.org Expert Reviews FEBRUARY 2018 American Journal of Obstetrics & Gynecology S839 100.

Cited by

Sorted by citations

Related

Authors
Groom, K. M., & David, A. L.
Affiliations
  • University of Auckland (NZ)
  • National Institute for Health and Care Research (GB)
Corresponding author
Groom, Katie M.
ORCID
Venue
American Journal of Obstetrics and Gynecology
Publisher
Elsevier BV
Published
2018-02
Volume
218
Issue
2
Pages
S829-S840
ISSN
0002-9378 (ISSN-L)
DOI
10.1016/j.ajog.2017.11.565
OpenAlex
W2771670745
Semantic Scholar
4e35bb0af4df34be165156bd6fb43be104a47d07
Cited by
170
References
135
Citations by year
2026: 7 · 2025: 17 · 2024: 16 · 2023: 25 · 2022: 15 · 2021: 33 · 2020: 27 · 2019: 20 · 2018: 10
FWCI
2.65
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal of Obstetrics and Gynecology (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
European Commission
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
Keywords
fetal growth restriction, aspirin, low molecular weight heparin, preeclampsia, uteroplacental circulation, spiral artery remodeling, placental ischemia, sildenafil, phosphodiesterase-5 inhibitors, nitric oxide, corticosteroids
MeSH terms
Anticoagulants, Aspirin, Female, Fetal Growth Retardation, Heparin, Heparin, Low-Molecular-Weight, Humans, Placental Insufficiency, Placentation, Platelet Aggregation Inhibitors, Pregnancy, Genetic Therapy, Vascular Endothelial Growth Factor A, Phosphodiesterase 5 Inhibitors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review